TW200927115A - Aryl-and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use - Google Patents

Abstract

The present invention relates to compounds defined by formula I wherein the groups R1 to R3, X, m, n and o are defined as in claim 1, possessing valuable pharmacological activity. Particularly the compounds are inhibitors of 11β -hydroxysteroid dehydrogenase (HSD) 1 and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this enzyme, such as metabolic diseases, in particular diabetes type 2, obesity and dyslipidemia.

Description

200927115 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to compounds derived from the following chemically-structured compounds defined by Formula I,

Wherein the groups R1 to R3, X, m, η and lanthanide are as defined hereinafter, including φ, its tautomers, stereoisomers thereof, mixtures thereof and salts thereof. The invention further relates to pharmaceutical compositions comprising a compound of formula I according to the invention, and to the use of a compound of the invention for the preparation of a pharmaceutical composition for the treatment of a metabolic disorder. Furthermore, the invention relates to a process for the preparation of a pharmaceutical composition and a compound of the invention. [Prior Art] In the literature, a compound having an inhibitory effect on the enzyme 11β-hydroxysteroid dehydrogenase (HSD) 1 has been proposed for the treatment of metabolic syndrome, particularly type 2 sugar ® urinary disease, obesity, and dyslipidemia. In the scientific publication Jcia PZ/armacewhca 1982, 3Ρ, pp. 61-64 and Jcia Ρσ/om'ae P/zarmacewi/ca 1986, 43, pp. 403-405, the following synthesis may be described as having various pharmacological activities, in particular Analgesic activity of benzomorphin:

1^=08(;,2,3-dimercaptoanilide, anilino, ethylamino, 3-methylsulfanylanilide 135590.doc 200927115 Scientific publication C/zew. 1976, 7 0P, The following microbiological transformation of benzomorphinane is reported on page 2657-2669:

Scientific publication Ruler eiero eye/es 1980, /4, pp. 1983-1988 describes the method of synthesizing the following heteromorphinane:

In Scientific Publications 2007, <53, pp. 7523-7531 and 2007, pp. 161-163, it is reported that the pure enantiomers of the following benzomorphin are used as intermediates (+)- and ( -) _alpha morphine synthesis (formal synthesis):

Patent DE 23 38 369 describes the preparation of microbenzol of the following general formula 135590.doc 200927115 CC biological hydroxylation method

/. , y where Ri, R2, Q, and z are as described herein in WO 03/097608, describing opium and opioid-like compounds of the general formula RAX (wherein R, A and X are as defined herein) For the treatment and prevention of septic shock and other conditions. In particular, A represents a benzoic acid of the following formula:

In US 4,108,857, a stupid morphinane derivative of the formula

X3 N R R1 = lower alkyl R2 = H, lower alkyl R3 = especially pyridyl described as having anticonvulsant, central nervous system inhibition and diuretic 0 activity in DE 23 54 002

The definition of a strepto-morphinan derivative of the general formula 'and R4 is 2-methoxymethyl-2-yl) is described for the preparation of a phase (wherein R1, R2, R3 and R5 are as defined herein) -3-yl or 3-methoxymethylcarbamate 135590.doc 200927115 should be an intermediate of N-bromomethyl-benzomorphine. In DE 2 229 695, the following formula is stupid and morphine Burning derivative

RO

(wherein R, R1, R2, R3 and γ are as defined herein) are described as intermediates in the preparation of benzomorphin which is suitable for use as an analgesic and antitussive.

In DE 2 1〇8 954, the stupid derivative of the following formula

(wherein R', R丨 and z are as defined herein) are primarily described as possible intermediates for the preparation of benzoic materials which have valuable therapeutic properties. In DE 2 105 743, spleen and s ice 1 from T to a benzomorphan derivative of the formula

(Different, RS and 2 are the main intervening substances of benzomorphan such as analgesic activity in the text. 4 is prepared by having a tricyclic nitriding #L analgesic of 135590 which can be described in US Pat. No. 3,703,529. .doc 200927115

(wherein R, R1, R2, X and Y are as defined herein). The inventors did not realize that the benzophenanthrene non-calcined fluorenyl-aryl- or heteropolyalkylene derivative was described as an 11β-hydroxysteroid dehydrogenase (HSD) 1 inhibitor. SUMMARY OF THE INVENTION The object of the present invention

The object of the present invention is to find new benzomorphine or related compounds, especially those which are active against the enzyme 11β-hydroxysteroid dehydrogenase (HSD) 1. Another object of the present invention is to find that the enzyme, base-alcohol dehydrogenase (HSD) 1 has an active and/or in vivo inhibitory effect and has suitable pharmacological and pharmacokinetic properties. Or related compounds. The present invention m provides a novel pharmaceutical composition suitable for the prevention and/or treatment of metabolic diseases, particularly diabetes and dyslipidemia. Other purposes of the month are apparent to those skilled in the art from the above discussion. OBJECTS OF THE INVENTION The present invention, in its broadest embodiment, relates to a compound having a chemical structure compound derived from the formula I, which is defined by the formula I.

135590.doc 200927115 wherein R1 represents an aryl or heteroaryl group, and the aryl group means a phenyl or naphthyl group, and the heteroaryl group means a pyrrolyl group, a furyl group, a thienyl group, a pyridyl group, a fluorenyl group. , benzo11-furanyl, benzoxenyl, fluorenyl, isoindolyl or pyrrolyl, furyl, thienyl, pyridyl, wherein 1 or 2 is CH substituted by N, or fluorenyl , benzofuranyl, benzothienyl, quinolyl or isoquinolyl, wherein 1 to 3 CH are replaced by N, or 1,2-dihydro-2-oxo-pyridyl, 1,4 - dihydro-4-o-oxy-pyridyl, 2,3 -monox-3-oxo-sole, 1,2,3,6-tetraki-3,6-di-oxy-anthracene Zinyl, 1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-indolyl-pyrimidinyl, iota, 2,3,4-tetrahydro-2,4- Bilateral oxy _ mouth oc, 1,2-dihydro 2 _ oxy-pyrazinyl, i, 2,3,4-tetrahydro 2'3 · di-oxy-pyridinyl, Dihydroindenyl, indoleoxy-indoline Q « violent, 2,3-dihydro-indenyl, 2,3-dihydro-1H, fluorenyl, 2,3-dihydrogenoxy - mercapto, 2,3-dihydro-1-oxo-isoindenyl, 2,3-dihydrobenzo- Furanyl, 2,3-dihydro-2-o-oxy-177-benzo-saltyl, 2,3-dihydro-2-oxo-benzoxazolyl, benzo[1,3] Di-dioxolyl, 2-oxo-oxybenzo[1,3]dioxolane, m#·tetrahydro-naphthyl, 1,2,3,4-tetrahydrogen -quinolinyl, 1,2,3,4-tetrahydro-2-oxo-quinolinyl, indole, 2-dihydro-2-oxo-indolyl, dihydro-4-side oxygen -Quinolinyl, 1,2,3,4-tetra 135590.doc _ 11 · 200927115 Hydrogen-isoquinolinyl, 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl 1,2-dihydro-1-oxo-isoquinolyl, 1,4-dihydro-4-iso-oxy-4-yl, 1,2-dihydro-2. oxo-quino Oxazolinyl, 1,4-dihydro-4-oxo-quinazolinyl, 1,2,3,4-tetrahydro-2,4-di-oxy-quinazolinyl, 1,2 - dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-3-isooxy-musophilic, 1,2,3,4-tetrahydro-2,3 - two-side oxy-quinoxalinyl, 1,2-dihydro-1-oxo-pyridazinyl, iota, 2,3,4-tetrahydro-1,4-di-oxy-pyridazine Base, sulfhydryl, coumarinyl, 2,3-dihydro-benzo[1,4]nonedioxacyclo-yl or 3,4-diaza-3-oxo-2 7-benzene [1,4] ° Ethyl, wherein the above aromatic or heteroaryl ring is optionally substituted by one R4, one to four identical or different R5 and one R6, and all heteroaromatic rings are bonded to the carbonyl via a carbon atom, R2 And R3 together with the double bond to which it is attached represent a benzo ring which is optionally substituted by R7, R8 and R9, and optionally substituted by R7, R8 and R9 to bite the ring, optionally as selected from R7. , and the substituents of R9 are substituted by pyrrole and sulphate 11 sulphate, sigh, sputum, and bite or " 嗓 嗓, depending on the case, substituted by pyridazole, imidazolium, Izolozepine, thiazide, isoxazole or isothiazolocarb, or optionally substituted by 1, 4 or 3, optionally substituted with one to three R10 substituted phenyl groups, optionally with C.. Oxazino ring, R represents fluorine, gas, desert moth,

Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxy, Cl-4 alkoxy 135590.doc -12- 200927115, nitro, amine, C!.3 alkylamino, two (C).3 alkyl)amino group, pyroline-1-yl group, 2-sided oxygen ratio η each bite-1-yl group, "bottom π-dec-1-yl group, 2-sided oxy group bite -1-yl, 吓*-4-yl, 3-sided oxy-oxalin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-side oxygen -Piperazin-1-yl, '(Cualkyl)-piperazin-1-yl, '(Cw alkylcarbonyl)-piperazin-1-yl, 4-(C3-6cycloalkyl) - 嗓-1_ base, 4-(CBu 4 oxycarbonyl)-piperazin-1-yl, '(Cw alkylsulfonyl)-piperazin-1-yl, 2-decyloxy -'(Cualkyl)-piperazin-1-yl, 3-o-oxy-4-((:,-3-alkyl)-tour -1-yl"

Cj-3 alkyl-carbonylamino, (hetero)aryl-carbonylamino, (hetero)aryl-Cm alkylcarbonylamino, Ch alkoxy-carbonylamino, amine amylamine, Cl.3 alkyl-amino-arylamino, bis(Cl.3 leu)-amino-amino group, 11-Butyl-1-yl-amino-amino group, britylene-based Amino, morphine-4-yl-arylamino, "• 嗓 嗓-1-yl-monoamino, 4-(〇1-3alkyl)_派11秦_1_基_基基Amino, hydrazine 1.3 alkyl _ continual amine amine group, amino sulfonylamino group, CN3 alkylamino-sulfonylamino group, bis(Cl _3 •) yl group - aryl amine Base, 咐·洛咬_1_基-Continuous-glycosylamino, ketone-1-yl-carboxylamino, morphine-4-yl-carboxylamino, piperazin-1-yl- Sulfhydrylamino group, 4-((:.3 alkyl)-piperazin-1-yl-sulfonylamino group, (C,.3 alkoxy-carbonylamino)carbonylamino group, (hetero Arylsulfonylamino, (hetero)aryl-Cw alkyl-sulfonylamino, ISKCw alkyl)-(:,-3 alkylcarbonylamino, N-(Cn3 alkyl)- (hetero)arylcarbonylamino, NJCh alkyl)·(hetero)aryl-Cw alkyl- 135590.doc -13 - 200927115 Amino group, N-CCw alkyl)-Ci-3 alkoxy-carbonylamino group, N-(aminocarbonyl)-(:1.3 alkylamino group, >^((:1.3 alkyl-aminocarbonyl) )_(:1.3 alkylamino group, N-[bis(Ci.3 alkyl)aminocarbonyl 1-6.3 alkylamino group, N-(Cu alkyl)-(:, .3 alkyl-sulfonate) Amino group, NJCi.3 alkyl doped) arylsulfonylamino group, alkyl)-(hetero)aryl-CN3 alkyl-sulfonylamino group, pendant oxy-m- 1-based, 2,4-di-oxy-β-salt-1-yl, 2,5-di-oxy-imidazolidin-1-yl, 2-sided oxy-hexahydropyrimidine-fluorenyl Wherein the nitrogen atom at position 3 of the above group is optionally substituted with a methyl group or an ethyl group, a gas group, a thiol group, a Ci-3 alkoxy group, an amino group, a Ci_3H1 group, an amine group Base, bis((^1-3 alkyl)-amino group, 11-buty-1-yl-carbonyl, piperidin-1-ylcarbonyl, morpholin-4-yl-carbonyl, piperazine- L-yl-carbonyl, '(Cw alkyl)-piperazin-1-yl-carbonyl, (hetero)arylaminocarbonyl, N-(CN3 alkyl)·(hetero)arylaminocarbonyl, (hetero ) aryl-Cm alkylaminocarbonyl, N-(CN3 alkyl)·(hetero)aryl-(^-3 alkylamine Base carbonyl

Ci-3alkyl-aryl, (hetero)aryl-yl, carboxy-Cw alkyl, C..3 alkoxy-carbonyl-Cw alkyl, cyano C!-3 alkyl, amine carbonyl-Cw alkyl, cN3 alkyl-aminocarbonyl-C 1 -3 alkyl, one (C 1 -3 alkyl)-amino thiol _ C 1.3 yard base, 11 bilot bite 1-yl- carbonyl-Ci.3 alkyl, piperidin-1-yl-carbonyl-Cw alkyl, morpholin-4-yl-mono-Ci.3 alkyl, pyrazin-1-yl-yl-c丨_ 3 alkyl, 4-135590.doc -14- 200927115 carboxy-Cy alkoxy, Cl_3 alkoxy-carbonyl-Cw alkoxy, cyano-Ci_3 alkoxy, amino-carbonyl-Cl3 alkoxy, D.3 alkyl-aminocarbonyl-Cw alkoxy, bis(c^3 alkyl)-amino-carbonyl-Ci-3 alkoxy, pyrrolidin-1yl-carbonyl-Cl_3 alkyl-oxygen , piperidin-1-yl-carbonyl-C 1 -3 alkoxy, morphine-4-yl-aryl-Ci-3 -alkyl-lactyl, oxazol-1-yl-carbonyl-Cw Oxyl, 4-(Ci-3 alkyl)-piperazin-1-yl-carbonyl-Ci.3 alkoxy, hydroxy-Cw alkyl, Cw alkoxy-CN3 alkyl, amine-Cw alkane , C 1-3 alkylamino-C 1_3 alkyl, bis(C 1-3 alkyl)-amino-C 1-3 alkyl, pyrrolidin-1-yl-Cw alkyl, 2-side Oxy-pyrrolidine- 1-yl-C 1 -3 alkyl, ketone-1-yl-Ci-3 alkyl, 2-butyryl-nitopic-1-yl_Cw alkyl, morpholin-4-yl-Cw Alkyl, 3-o-oxo-morpholin-4-yl-(^1.3 alkyl, '1 嗓 嗓 _ _ _ (^1.3 alkyl, 2-sided oxy-Nang-qin-1-yl -C 1.3 炫, 3-tertiary-slightly -1 -yl-Ci.3 alkyl, 4-(Ci ·3 炫)-旅嗓-1·基- Ci_3 yard, 2-side oxygen Base - 4-(Ci-3 alkyl)_1* bottom ° Qin·· 1-yl-Ci-3 alkyl, 3-sided oxy-4-(Ci-3 alkyl)-° bottom ° Qin-1 -yl-C!-3_β alkyl, C, .3 alkylcarbonylamino-Cw alkyl, arylcarbonylamino-Cw alkyl, via-<31-3, methoxy, 匚1- 3 alkoxy-匚1.3 alkoxy, (1; 1.3 alkylthio-Ci-3 alkoxy, Ci·3 alkyl thiol-Ci·3 alkoxy, (1.3 1.3 sulfonate) Mercapto-匚1-3 **oxy, amino group <1_3 ))oxy, 〇1-3 alkylamino-Cl-3 alkoxy, bis(Cl-3alkyl)-amine- Cw alkoxy, β 比哈B定-1-yl-C!_3 alkoxy, 2-o-oxy-D ratio l--1-yl-135590.doc -15· 200927115

Cl-3 alkoxylate, bottom bit-1-yl-Cl-3 alkoxy group, 2-sided oxy-n-bending _ 1-yl-Ci_3 alkoxy group, morphine _4-yl-Ci_3 Oxyl, 3-oxooxy-Callin-4-yl-C 1.3 alkoxy, quinoxa-1-yl-C 1.3 alkoxy, 2-oxo-piperazin-1-yl-Cw Alkoxy, 3-o-oxy-piperazin-1-yl-Cw hexyloxy, 4-(Ci.3 alkyl)-Becken-1-yl-C1-3 alkoxy, 2-side Oxy-4-(Ci-3 alkyl)-Brigade-1_yl_Ci-3 alkoxy, 3-sideoxy-4_(〇1_3 alkyl)_派11秦-1_基_〇 1-3 alkoxy group, (^1-3 thiol group, 匚1.3 succinyl ketone base, (^1-3 smelt base Φ base, C, ·3 alkyl sulfonyloxy group, (hetero)arylsulfonyl, (hetero)arylsulfonyloxy, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl., aminosulfonyl , Cw alkyl-aminosulfonyl, bis(Cw alkyl)-aminosulfonyl, pyrrolidin-1-yl-hydrazinyl, alkidine-1-ylsulfonyl, holly-4 -yl-sulfonyl, piperazine-buyl-sulfonyl, 4-(c)-3-alkyl)-^11-heptan-1-yl-continuous, difluoromethyl, trifluoromethyl, Fluoromethoxy, trifluoromethoxy, 2,2,2-di 1-hydroxyethyl, 2,2,2-trifluoro-1-hydroxy-1.methylethyl, 2,2,2·trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl , C3·6 cycloalkyl, c3-6 cycloalkoxy 'C3.6 cycloalkyl-c〗.3 alkyl, C3 6 cycloalkyl-Cw alkoxy, (hetero)aryl, (hetero) Aryloxy, (hetero)aryl-Cu alkyl, (hetero)aryl-Cl.3 alkoxy, (hetero)aryloxy-Cmalkyl, or tetrahydrofuran-3-yloxy, tetrahydroper __3_yloxy, tetrahydropiperidin-4-yloxy, tetrahydrofuranyl-C丨-3 alkoxy, tetrahydropyranyl 135590.doc -16 - 200927115

Cl-3 alkoxy, wherein the azetidin-1 -yl, pyrrolidin-1 -yl and piperidinyl 1-yl moiety is optionally selected from methyl, ethyl or decyloxy by one or two Substituted with a radical, a radical or a group of an oxy group, and wherein the above piperazin-1-yl and morpholin-4-yl moiety is optionally selected from one or two selected from the group consisting of decyl, ethyl or methoxymethyl a group substituted, and wherein the above (hetero)aryl group is a phenyl group, a naphthyl group, a fluorenyl group, a furyl group, a porphinyl group, a tetradyl group, a β-bite group, a fluorene group, a benzofluorene group A benzothiophenyl group, a quinolyl group, an isoquinolyl group or a D-l- yl group. a fluoromethyl group, a fluorenyl group, a D-pyridyl group, wherein 1 or 2 CHs are replaced by N, or a fluorenyl group, a benzofuranyl group, a benzothienyl group, a quinolyl group, an isoindolyl group, wherein 1 to 3 CH substituted by N, or 1,2 - wind-2 - side oxy-specific η group, 1,4 - dihydro-4 - sideoxy - π * pyridine, 2,3-dihydro - 3-sided oxy-pyridazinyl, 1,2,3,6-tetrahydro-3,6-di-oxy-pyridazinyl, 1,2-dihydro-2-indolyl-pyrimidinyl, 3 _ Dihydro-4-oxo-pyrimidinyl, iota, 2,3,4-tetrahydro-2,4-di-oxy-pyrimidinyl, I,2-dihydro-2-indolyl- Pyrazinyl, I, 2,3,4·tetrahydro-2.3-di-oxy-pyrazinyl, 2,3-dihydro-2-oxo-indenyl, 2.3-dihydrobenzofuran , 2,3-dihydro-2-oxo-oxime/f-benzoxazolyl, 2,3-dihydro-2-sideoxy-benzoxazolyl, 1,2-dihydro _2_Sideoxy-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl, iota, 2-dihydro-bromo-isoquinolinyl, 1,4-di Hydrogen-4-oxooxy-4-phenyloxy, hydrazine, 2-dihydro-2-oxo-quinazolinyl, 1>4-dihydro-4-yloxy-quinazoline 135590.doc -17 · 200927115 base, 1,2,3,4-tetrazo-2,4-dioxy- Indole, 1,2-diaza-2-oxoquinoxalinyl, iota, 2,3,4-tetrahydro-3-oxo-oxalinyl, 1,2,3,4 -tetrahydro-2,3-di-oxyl-oxalinyl, 1,2-dihydro-1-oxo-pyridazinyl, 1,2,3,4-tetrahydro-1,4- Bilateral oxy-carbonyl group, fluorenyl group, coumarin group, 2,3-dihydro-benzopyrene, 4]dioxanyl group, 3,4-dihydro-3- side Oxy-2//-benzo[1,4]oxazinyl, and wherein the above (hetero)aryl group may be substituted by one or two R10 which may be the same or different, and may be the same or different R5 and R6 Represents halogen, Cl_3 alkyl, C2-3 alkynyl, trifluoromethyl, hydroxy, C..3 alkoxy, cyano or R. _. R is bonded to an adjacent carbon atom to form a methylene group. Dioxy, difluoromethylenedioxy, ethylenedioxy, C3-5 alkyl, or R together with R to the adjacent carbon atom may form together with the carbon atom to which they are attached. More than the saliva, the microphone β sitting and.恶β sits and sighs, sighs, and η is sinister and or isothiazide is cyclized, depending on the situation, C..3 alkyl, trifluoromethyl, amine, C, ·3, a group of amines, two (C)·3 alkyl)amine, hydroxyl, Cy alkoxy are deuterated, R7 represents fluorine, gas, bromine, iodine,

Cm alkyl, hydroxy, Cl_4 alkoxy, nitro, amine, Ci.3 alkylamino, bis(Cw alkyl)amine, piroxicam-1, 2-sided oxy-η Bilo bite _1_ base, slightly bite _1_ base, 2_side oxy-piperidin-1-yl, morpholine _4_yl, 3-sided oxy-morpholin-4-yl, azide -1-yl, 2-oxooxypiperazin-1-yl, 3-oxo-piperazinyl, 4-(C,3 alkyl)-piperazine-indolyl, 4-(C 4-alkylcarbonyl)-piperazine_135590.doc -18- 200927115 1-yl, 4-(C3_6 cycloalkylcarbonyl)-piperazin-1-yl, 4-((^-4 alkoxycarbonyl) - piperazin-1-yl, 4-((^-4 alkylsulfonyl)-piperazin-1-yl, 2-oxoalkyl)piperazin-1-yl, 3-side oxygen 4-((^.3 alkyl)-** 嘻 嘻-1-yl 1 C!-3 alkyl-carbonylamino, (hetero)aryl-carbonylamino, (hetero)aryl-Cw Alkyl carbonylamino, Cw alkoxy-carbonylamino, aminocarbonylamino, CN3 alkyl-aminocarbonylamino, bis(Cw alkyl)aminocarbonylamino, pyrrolidin-1-yl -carbonylamino, piperidin-1-yl-carbonyl0-amino, morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino, 4-(C^alkyl)-piperazine -1-yl-carbonylamino group Cw alkyl-sulfonylamino group, aminosulfonylamino group, c,_3 alkylamino-sulfonylamino group, bis(CN3 alkyl)amino-sulfonylamino group, ° ratio Pyridin-1-yl-sulfonic acid amine, slightly 11-decyl-1-yl-arylamino group, morphin-4-yl-cross-branched amine group, 0 bottom, Qin-1-yl- Amino group, 4-(Ci_3 alkyl)-β-end 11 Qin-1-yl-continuous amine group, (Cw alkoxy-carbonylamino)carbonylamino group, (hetero) aryl rock orange amine (hetero)aryl-Ci-3 alkyl-continuous mercaptoamine ' ® Ν-γ υ alkyl)-Cw alkyl-carbonylamino group, ISKCw alkyl)-(hetero)arylcarbonylamino group, N_(C,-3alkyl)-(hetero)aryl-Cw alkyl·carbonylamino, NKC!.3 alkyl)-(^-3 alkoxy-carbonylamino, N-(aminocarbonyl) )-(^-3alkylamino group, NKCw alkyl-aminocarbonyl)-(:,.3 alkylamino group, N-[di(C__3 alkyl)aminocarbonylalkylamino group, N -(Ci-3 alkyl VCu alkyl-sulfonylamino, N-CCw alkyl)-(hetero)arylalkylamino, N-(Ci-3alkyl)-(hetero) - Ci_3 alkyl-organylamino 5 135590.doc • 19- 200927115 pendant oxy-imidazolidin-1-yl, 2,4-dioxy -Imidazolidin-1-yl, 2,5-di-oxy-mi-indole 1,3-decyl, 2-sided oxy-hexahydropyrimidin-1-yl, wherein the nitrogen atom at position 3 of the above group Substituted by methyl or ethyl, cyano, (hydroxyimino)aminomethyl, (Ch alkoxyimino) aminomethyl, carboxyl, Cm alkoxy-carbonyl, aminocarbonyl , Cw alkyl-aminocarbonyl, bis(CN3 alkyl)-aminocarbonyl, pyrrolidin-1-yl-yl, brioline 11-meryl, morphin-4-yl-yl, british -1-yl-monoyl, 4-(Ci.3 alkyl)-slightly ~ Qin-1-yl-number base

Ch alkylcarbonyl, (hetero)aryl-carbonyl, thio-Ci-3 hexyl, Ci_3 alkoxy-hexyl-Ci-3 alkyl, cyano-Cw alkyl, aminocarbonyl- Cw alkyl, Cw alkyl-aminocarbonyl-(31-3 alkyl, bis((1.3)alkyl)-amino group-(111.3Han 1 base, 11 lbino-bu-ki-carbonyl-Cw-alkane , piperidin-1-yl-carbonyl-Cw alkyl, morpholin-4-yl-yl-Cl.3 Hyun•yl, slightly 11-methyl-1-yl-s-yl-Ci_3 alkyl, 4- (〇1_3烧基)-旅°秦-1-yl-class _ ke-〇1.3 alkyl, ® carboxy-Cw alkoxy, Cw alkoxy-carbonyl-Cw alkoxy, cyano-Cw alkoxy , amino-carbonyl-C, .3 alkoxy, Cm alkyl-aminocarbonyl-Cw alkoxy, bis(Cw alkyl)-amino-carbonyl-Cm alkoxy, °Bilo bite- 1·基-数基-C!_3院基-Alkyl, ketone-1-yl-poly(yl)-C 1 -3 oxime, oxime-singyl-Ci_3 alkyl oxy, 派17 ························································ Alkyl, amino-Cw alkane 135590.doc -20· 200927115 base, 匚1.3 alkylamino group _(^1_3 炫基,二(<1:1-3 alkyl)- Base —匸1-3 alkyl, pyrrolidin-1-yl-Cm alkyl, Cm alkylcarbonyl-amino-Cu alkyl, Ν-βυalkyl)-(:,-4 alkylcarbonyl-amino group -Ci-3 alkyl, 2-sided oxy-β, butyl-1-yl-Ci-3, succinyl-1-yl-Ci-3, 2-sided oxy-D -1-yl-C!-3 yard base, morphine-4-yl-Ci-3 alkyl, 3-sided oxy-morphine-4-yl-C 1-3 yard, call _1_ —C 1-3 alkyl, 2-oxo-piperazin-1-yl-C!-3 alkyl, 3-o-oxy-piperazin-1-yl-Cw alkyl, 4-(C !-3 alkyl)-piperazin-1-yl-Cw alkyl, 2-sided oxime -4-(CN3 alkyl)-piperazin-1-yl-C-3-alkyl, 3· side Oxy-4-(Ci-3 alkyl)-Break-qin-1-yl-C.3 alkyl-based thiol-C 1 _ 3 ||oxy, C 1 _ 3 alkoxy _ C 1 _ 3 炫 * oxy, C 1 · 3 alkylthio-C alkoxy, C, .3 alkyl sulfinyl-C!. 3 alkoxy, 〇 1.3 yard base _ 匚 1.3 Hyun>oxy group, amine group 匚 1-3 1-3> oxy group, 匸1-3 alkylamino group-Cw alkoxy group, bis(Cw alkyl)-amino group-cN3 alkoxy group, °tb洛-1-基-C〗 _3 acetoxy, 2-oxooxyl oxime-1-yl-Cw alkoxy, piperidin-1-yl-CN3 alkoxy, 2-sided oxy- Piperidine-® 1-yl- Cl.3 alkoxy, morphine-4-yl-Ci-3 alkoxy, 3-oxo-morpholine-4-yl-Cw alkoxy, piperazin-1-yl-Cw alkoxy , 2-sided oxy-n-n-indol-1-yl-Ci.3 alkoxy, 3-oxo-p-but-1-yl-Ci-3 alkoxy, '(Cualkyl)-peri Pyrazin-1-yl-Ci.3 alkoxy, 2-o-oxy-4-(Ci.3 alkyl)-p-I'l-yl-Ci_3, oxy- 3-oxy-4- (Ci_3 烧基)_派°秦_1_基_Ci-3 alkoxy,

Cw alkylthio, Cw alkyl sulfinyl, Ci. 3 alkyl sulfonyl, C _ 3 alkyl sulfonyloxy, (hetero) aryl sulfonyl, (hetero) aryl 135590. Doc -21 - 200927115 Continuation of decyloxy, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, aminosulfonyl, Cw alkyl-aminosulfonyl , bis(Cl_3 alkyl)_aminosulfonyl, pyrrolidine-4-yl-sulfonyl, piperidine β1_*_sulfonyl, morpholine-4-yl·thenyl, piperazin-1-yl - 醯 醯, 4-(CK3 alkyl)-旅噃-1-基-Continued 醯基, ❹

Difluorodecyl, trifluorodecyl, difluorodecyloxy, trifluoromethoxy, 2,2,2-difluoro-1-hydroxyethyl, 2,2,2-trifluoro·1•hydroxyl q • mercaptoethyl, 2,2,2-trifluoro-hydroxy-1-(trifluoromethyl)ethyl, C3_6 cycloalkyl, (:3.6 cycloalkoxy, C3_6 cycloalkyl-Cm alkyl, C3 6 cycloalkyl-Ci 3 alkoxy, (hetero)aryl, (hetero)aryloxy, (hetero)aryl-Ci 3 alkyl, (hetero)aryl-Cw alkoxy, (hetero) Aryloxy-Ci 3 alkyl, or tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C丨-3 alkoxy , tetrahydropyranyl·Ci-3 alkoxy, wherein the above (hetero) 3⁄4• group is as defined above, and the same or different R8 and p9 gases are halogen, CU3 alkyl, trifluoromethyl a hydroxyl group, a Ch oxyloxy group, a cyano group or R together with R right to an adjacent carbon atom may additionally be a fluorenylenedioxydienedioxy group, an ethylenedioxy group, and an extended alkyl group. , or R, together with R right, binds to the adjacent ί ι έ γ π. The neighboring atom can also form a stupid, biting, and whispering together with the carbon atom to which it is attached. Open azetidin, pyrazino, pyridazine, pyrazolo, imidazolium, triazole and oxazolidine, thiazolidine, isoxazole or 135590.doc • 22· 200927115 isothiazolidine ring, Depending on the case, one L and/or one or two independently selected from halogen, c丨.3 alkyl, trifluoromethyl, amine, c丨_3 alkylamino, diπ"alkyl)amine Substituted by a substituent of a hydroxyl group or a C3 alkoxy group, L is L1 or L2, and L represents a halogen, a c6 alkyl group, a C3.6 cycloalkyl group, a piperidinyl group, and an i_(c丨3 alkyl group). )-°Chen, base group, bottom bite group, tetrahydrocarbamate, difluoromethyl, trifluoromethyl, cyano, nitro, amine, ethenylaminomethylsulfonate Mercaptoamine, carboxyl, alkoxycarbonyl, aminocarbonyl, Ci3 alkylaminocarbonyl, bis(C1.3 alkyl)-aminocarbonyl, aminosulfonyl, methylthio, A a sulfinyl group, a methylsulfonyl group, a hydroxyl group, a Cw alkoxy group, a difluoromethoxy group or a trifluoromethoxy group, and L2 represents a phenyl or pyrrolyl group, a furyl group, a thienyl group, a pyridyl group, wherein '1 or 2 CHs in any of these groups are replaced by n atoms as appropriate Or 1,2-dihydro-2-oxo-pyridyl, dihydro-4-yloxy-pyridyl, 2,3·dihydro-3, pendant oxy-pyridazinyl, 1,2, 3,6-tetrahydro-3,6-di-oxy-chizinyl, 1,2-monohydro-2-oxo-mouth butyl, 3,4-dihydro-4- oxo- Pyrimidinyl, 1,2,3,4-tetrahydro-2,4-di-oxy-pyrimidinyl or 1,2-dihydro-2-yloxy-oxazinyl, wherein the above is given under L2 And the groups are each substituted by one or two groups independently selected from the group consisting of fluorine, gas, Cl_3 alkyl, difluoroindenyl, trimethylmethyl, cyano, amine, ethenyl Amine group, methylsulfonic acid amine group, m group, c!·4 alkoxycarbonyl group, aminocarbonyl group, Cl.3 alkylaminocarbonyl group, di(C!.3) group, aminocarbonyl group, Hydroxy, Cw alkoxy, difluoroanthracene 135590.doc -23- 200927115 oxy and trifluoromethoxy, R10 is R1G' or R1G·', and R1<r represents halogen, C, ·3 alkyl, two Fluoromethyl, trifluoromethyl, cyano, nitro, amine, etidylamino, decylsulfonylamino, carboxyl, Cl_4 alkoxycarbonyl, aminocarbonyl, Cw alkylaminocarbonyl , bis(Cl_3 alkyl)-aminocarbonyl , aminosulfonyl, decylthio, decylsulfinyl, methylsulfonyl, hydroxy, C!-3 alkoxy, difluoromethoxy or trifluoromethoxy, O RlG 'Indicating pyrrolyl, furyl, thienyl, pyridyl' wherein, in any of these groups, 1 or 2 CH is optionally replaced by a N atom, or a π 丨 n phenyl group, a benzofluorenyl group, Benzene-derived phenyl, sulfonyl, isoindolinyl, wherein in any of these groups, 1 to 3 CH are optionally replaced by N atoms, or phenyl, naphthyl, tetrazolyl, 1,2 _Dihydro-2·sideoxy-pyridyl, hydrazine, 4-dihydro-4-oxo-pyridyl, 2,3-dihydro-3-yloxy-pyridazinyl, hydrazine, 2,3 ,6·tetrahydro-3,6-di-oxy-pyridazinyl, 1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-o-oxy-pyrimidinyl , ι, 2,3,4-tetrahydro-2,4-di-oxy-pyrimidinyl, 1,2-dihydro-2-oxoxy-pyridinyl, anthracene, 2,3,4-tetrahydrogen _ 2,3-di-oxy-pyrazinyl, 2,3-dihydro-2-oxo-indenyl, 2,3-dihydrobenzofuranyl, 2,3·dihydro-2 - side oxybenzimidazolyl, 2,3_monohydro-2-oxo-p-oxazolyl, anthracene, 2-dihydro- 2_Sideoxy-quinolyl, 1'4-dihydro-4-isooxy-quinolinyl, anthracene, 2_dihydro-indole_sideoxy-isoquinolinyl, 1'4-di Hydrogen-4-oxo- 4 phenyl group, anthracene, 2-dihydro-2-indolyl quinazolinyl, 1,4-dihydro-4-iso-oxy-quinazolinyl, 1, 2,3,4-tetrahydro-2,4-di 135590.doc •24· 200927115 oxo-quinazolinyl, 1,2-dihydro-2-oxoquinoxalinyl, 1>2 , 3,4_ tetrahydroxyloxy-quinoxalinyl, anthracene, 2,3,4-tetrahydro-2,3-dioxy-quinoxaline, 1,2-dihydro-1- side Oxy-pyridazinyl, tetrahydro-indole, anal di-oxo-pyridazinyl, fluorenyl, coumarinyl, 2,3-dihydro-p-benzo[1,4]dioxine Alkenyl or 3,4-dihydro-3-indolyl-2//-benzo[1,4]oxazinyl, ,-, and wherein any of the groups mentioned above under R10 are optionally independent Substituted by or two groups selected from the group consisting of dentate, Cw alkyl 'difluoromethyl}, trifluoromethyl, cyano, nitro, amine, ethyl hydrazino, methyl Sulfhydrylamino group, carboxyl group, Cw alkoxycarbonyl group, aminocarbonyl group, Ci 3 alkylaminocarbonyl group, di(Cl 3 alkyl)-aminocarbonyl group, Alkylsulfonic acid, methylthio, methylsulfinyl, methylsulfonyl, hydroxy, CN3 alkoxy, difluoromethoxy and trifluoromethoxy, X represents CH or N, m, η, 〇 represents 0, 1 or 2, and wherein the bicyclic core structure of the formula I is independently substituted by R" to R*4, wherein R11 represents fluorine, CN4 alkyl, (hetero)aryl, hydroxyl, Cm A grafted oxy group, a cyano group, a carboxyl group, a Cw alkoxycarbonyl group, an aminocarbonyl group, a c!-4 alkylamino group-carbonyl group, a bis(C!.4 alkyl)-aminocarbonyl group, a hydroxy-Ci 4 alkyl group Or Cw alkoxy-Ci_4 alkyl, wherein (hetero)aryl is as described above, R12 represents fluoro or fluorenyl, and the same or different R13 and R14 represent Cl_4 alkyl, 135590.doc • 25· 200927115 and at the same time the "base or excipient moiety" is a subdomain or non-branched bond, its tautomers, its stereoisomers, mixtures thereof and their salts, while excluding formulas II.1 to 11>8 Compound M4

Wherein R is any substituent, ^ is 匚 "alkyl, M2 and M3 are each independently hydrogen or Ci4 alkyl, hydrazine is hydrogen or a radical, hydrazine is hydrogen or a radical, and χτ 6 士 represents a phenyl group, It may be through one to three groups of substituents selected from the group consisting of the following substituents, a mercapto group, a pyridyl group, a nitro group, a cyano group, a tridylmethyl group, a methoxy group, a naphthyl group or a biphenyl group. Substituted by one to three substituents selected from the group consisting of halogen, alkyl, nitro, cyano, trifluoromethyl, methoxy, hexyl, which may be substituted by the following groups: a lignin, an alkyl group, a nitro group, an aryl group, a trifluoromethyl group, a methoxy group and NR, wherein R' and R, each independently of a hydrogen or an alkyl group, or together with a nitrogen atom, have a double 3 to 7 member alicyclic ring, 135590.doc -26 - 200927115 喧, q, isoquinolyl, 4-cyclohexylphenyl, 4-oxo-4H-咣" , benzothienyl, benzofuranyl, 5,6,7,8-tetrahydro-naphthalen-1-yl, 5,6,7,8-tetrahydro-naphthalene-2-yl, furyl, fluorenyl Butanyl, ethylfuranyl, methoxymethylfuranyl, Thienyl, methylthienyl or ethylthienyl,

® wherein M1 is Cw alkyl, M2 is hydrogen or Cw alkyl, M6 represents 2-ethoxycarbonyl phenyl, 2-ethylamino-phenyl, 2-phenylamino-phenyl, 2- (2,3-Dimethylphenylamino)-phenyl, 2-(3-methylthiophenylamino)-phenyl or. More than D,

Wherein R is hydrogen, cN6 alkyl, M1 is hydrogen or Cm alkyl, M4 is hydrogen or hydroxy, M6 is phenyl, nonylphenyl or decyloxyphenyl, 135590.doc -27· 200927115

The compound of the formula I of the present invention and a physiologically acceptable salt thereof have valuable pharmacological properties, and particularly have an inhibitory effect on the enzyme 11β-hydroxysteroid dehydrogenase (HSD) 1. The first aspect of the present invention is also directed to a physiologically acceptable salt of a hydrazine compound of the formula and an inorganic or organic acid, in addition to a salt of a compound of the formula π" to 118.

In a second aspect, the invention relates to a salt comprising at least one of the formula ( (except for the compounds encompassed by the formulae 11 to 88) or a physiologically acceptable salt of the invention, as appropriate, and one or more A pharmaceutical composition of an inert carrier and/or diluent. In a third aspect, the invention relates to a compound of formula j (including a compound of formula π" to Π8) or a physiologically acceptable salt thereof for use in the treatment or prevention of an enzyme 11β- A disease or condition affected by inhibition of hydroxysteroid dehydrogenase (HSD) i, such as a metabolic disorder. In a fourth aspect, the invention relates to at least one compound of the formula (including 135590.doc -28-200927115 comprising a compound encompassed by the formulae II.1 to II.8), or a physiologically acceptable salt thereof One of the uses for the preparation of a pharmaceutical composition suitable for treating or preventing a disease or condition (such as a metabolic disorder) which can be affected by inhibition of the enzyme 11β-hydroxysteroid dehydrogenase (HSD)! In a fifth aspect, the present invention relates to a method of preparing a pharmaceutical composition of the present invention, which is characterized in that a compound of the formula I (other than a compound encompassed by the formulae 11 to II·8) is obtained by a non-chemical method or One of its physiologically acceptable salts is incorporated into one or more inert carriers and/or diluents. In a sixth aspect, the invention relates to a process for the preparation of a compound of formula I (other than the compounds encompassed by formulae II.1 to II.8), characterized in that it is as defined above and below general formula! a compound, as the case may be, in the presence of a base or another additive, a compound of the formula

R3 into xS

Wherein the groups R2, R3 and X, m, η and 0 are as defined above and below; reacted V-CO-Y prepared in situ from the corresponding carboxylic acid, wherein Y is a leaving group and especially Non-fluorine i, gas, > odor, nitrogen, Ci_iQ alkoxy, 〇1_6 alkylthio, C2-4 alkenyloxy, c2.4 alkynyloxy, oxyaryl-triazole, oxygen Heteroaryl-triazole, heteroaryl, amber-yl-N-oxy, Ci.4 alkylcarbonyloxy, bis(Cmalkyl)aminocarbonyloxy, pyrrolylcarbonyloxy, piperidine Alkylcarbonyloxy, morpholinylcarbonyloxyl 135590.doc -29- 200927115 丞, bis(c丨-4alkyl)mercaptooxy, N,N,N',N'-tetra-(c丨4 : p group) alditol group, N,N,-dicyclohexyl alditol group, bis (Ci4 alkoxy 1 = fluorenyloxy group, bis(di-C!·4)-based fluorenyloxy group, And the alkyl, alkenyl and alkynyl groups mentioned in the above group definition are either alone or in combination with an alkyl group, an aryloxy group, a heteroarylthio group, an aryloxy group or a heterooxy group. As a part of another group, it may be mono- or polysubstituted by fluorine, gas, C. 3 alkyl or Ci 3 alkoxy, 3 The above-mentioned group; the aryl group mentioned in the meaning of t represents phenyl or naphthyl group alone or as part of another fai, and the heteroaryl group mentioned in the above group is used alone or as another group. In the part of the group, it means that η is more specific than the biting group, the puncturing base, the triazinyl group, the succinyl group, and the aryl group, the trisalyl group, the tetrazolyl group, the aryl group and the heteroaryl group are independently fluorine and gas. , bromine, Cw alkyl, Cl_3 alkoxy, nitro, cyano or bis(Cw alkyl)amine are mono- or polysubstituted, and R is as defined above and below, and if required simultaneously or subsequently cleavage Any of the groups used in the above reaction, ° if it is necessary to 'resolve the general-purpose compound thus obtained to its stereoisomerization, if necessary, to convert the general-purpose compound thus obtained into a salt thereof, especially for medical use. It is a physiologically acceptable salt thereof. 'The compounds of the invention obtained by the route can be subsequently converted into other compounds of the invention by a conventional method suitable for the conversion of functional groups. ^ 135590.doc -30- 200927115 Examples of transformation methods are provided in the following paragraphs. According to the invention, the compound of the formula I which comprises an amine group, an alkylamino group or an imine group can be converted into a brewing or continuation-based compound of the corresponding formula by deuteration or sulfonation; If a compound of the formula I comprising a hydroxyl group is obtained, it can be converted into a corresponding mercapto or sulfonyl compound of the formula I by deuteration or commercialization; if an amine group, an alkylamine group or an imine is obtained The compound of the formula I can be converted into the corresponding alkylated oxime of the formula I by in vivo or reduction; if a compound of the formula I comprising a nitro group is obtained, it can be converted by reduction a corresponding amine-based compound; if a compound of the formula I comprising an imine group is obtained, it can be converted to the corresponding N-amino-imino compound by nitration and subsequent reduction; if a Cw alkoxycarbonyl group is obtained a compound of the formula I can be converted to the corresponding carboxylic compound by cleavage of S; if a compound of the formula I comprising a carboxy group is obtained, it can be converted to the corresponding ester of the formula I by esterification; a compound of formula I comprising a carboxy or ester group, which It should be converted to the corresponding guanamine of formula I; if a compound of formula I containing an aromatic substructure is obtained, it can be reacted with a gas, bromine or iodine atom or a nitro group, sulfonic acid or by electrophilic substitution reaction. The thiol group is derivatized to the corresponding compound of the formula I; if a compound of the formula I comprising an aromatic amine group is obtained, it can be diazotized and subsequently cyanide, fluoride, vapor, bromide, hardened 135590.doc • 31 · 200927115 Substituting a diazo group for a compound, hydroxide, alkyl or hydrosulfide or azide to convert it to the corresponding formula cyano, fluoro, fluoro, bromo, iodo, μ a thiol or azide-based compound; if a compound of the formula I comprising an aromatic amine group is obtained, it can be replaced by diazotization followed by hydration with a suitable aryl nucleophile mediated by a suitable transition metal species a nitrogen group converts it to the corresponding aryl-derived aromatic compound of formula I; if obtained, includes an aromatic gas group, a bromo group, an iodine group, a trifluoromethylsulfonyloxy group, a decyloxy group or A compound of formula I, which is a hydrazine-based oxy group, can be obtained by using a transition metal A method of mediated by converting a respective group with an aryl, alkenyl, alkynyl or alkyl group to convert it to the corresponding aryl, alkenyl, alkynyl or alkyl derived compound of formula I; a compound of a gas group, a bromo group, an iodine group, a trifluoromethylsulfonyloxy group, a fluorinated oxy or a tosyloxy group, which may be substituted with a hydrogen to obtain an aromatic compound of the formula I; ❹ If a compound of formula I is obtained which comprises two adjacent heteroatoms which are an amine group and a hydroxyl, amine or sulfhydryl group, these heteroatoms may be bonded via a carboxyl carbon atom to form a cyclic oxime which may be an aromatic ring moiety. , imidate or iminothioester substructure; σ If a compound containing a cyano group is obtained, it can be converted into an aminoalkyl-derived Hb compound by reduction; The cyano compound of the formula I can be converted to the N-methyll base by treatment with hydroxylamine; if a compound of the formula I comprising an N-hydroxymethyl group is obtained, it can be obtained by 135590.doc • 32- 200927115 a group or related group treatment converts it to an oxadiazole derived compound of formula i; Obtaining a compound of the formula I comprising an aminocarbonyl group, which can be converted into a cyano compound of the corresponding formula by dehydration; if a compound of the formula I comprising a keto group or an aldehyde group is obtained, it can be The nuclear reagent reacts it to a corresponding hydroxyalkyl compound of the formula I; if a compound of the formula I comprising a keto group or an aldehyde group is obtained, it can be converted to the corresponding hydroxy compound of the formula I by reduction; A compound of the formula I comprising a cyano group can be converted to a tetrazolyl compound of the corresponding formula by reaction with an azide salt or a derivative; if a compound of the formula I comprising a nitro group is obtained, Converting it to the corresponding amino compound by reduction; and/or if a compound of the formula I comprising an amine group is obtained, it can be converted to the corresponding pyrrole by reaction with an indole, a 4-diamino compound or a synthon thereof. Substituting a compound of formula I. Subsequent esterification is conveniently carried out between 〇 and 丨5〇〇c, preferably between 〇 and 80 C, optionally in the presence of an acid such as hydrochloric acid or in a dehydrating agent such as acetoin Vinegar, sulphur sulfoxide, trimethyl gas decane, sulfuric acid, methane sulfonic acid, p-toluene sulfonic acid, phosphorus trichloride, phosphorus pentoxide, n, N'-dicyclohexylcarbodiimide, N, N , _ dicyclohexylcarbodiimide / oxime · by imine imine or i via benzotrien and in the case of additional 4-dimethylamino-(tetra), N, N, · a few Or a mixture of triphenyl squamous/tetracarbonated carbon in a solvent or solvent mixture (such as dioxin, dimethylformamide, benzene, toluene, benzene, tetrahydrobite, benzene/tetrahydrobite) Or methane 135590.doc -33· 200927115 is burned or particularly advantageously carried out in the corresponding alcohol. Subsequent vinegar formation can also be carried out by reacting a compound containing a carboxyl group with the corresponding alkyl halide. Or sulfonate depending on the temperature between 〇 and 15 〇〇C, preferably between 〇 and 80 ° C, optionally in the presence of a third organic base or in inorganic In the presence of a base or in the presence of a dehydrating agent (for example, isobutyl chloroformate, sulfoxide, dimethyl decane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trioxide, phosphorus pentoxide, N,N,_dicyclohexylcarbodiimide, n,n,_〇% hexylcarbodiimide/N-hydroxysuccinimide or 1·hydroxy·benzotriazole) and optionally In the presence of 4_dimethylamino-pyridine, N, N, carbonyldiimidazole or triphenylphosphine/carbon tetrachloride in a solvent or solvent mixture (such as dioxane, dimethyl decylamine) In the case of benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, the corresponding mercapto or sulfonyl derivative is used. The subsequent alkylation is optionally carried out at 150 and 150. (: between, preferably 〇 and 1 〇〇. at the temperature between ', depending on the situation in the presence of the third (4) or in the presence of an inorganic test in a solvent or solvent mixture (such as digastric, dimethyl In the case of methotrexate, benzene, toluene, benzene, tetrahydrogen M, stupid/tetrahydrocoke or dihydrogen, an alkylating agent such as a corresponding dentate or sulfonate, for example Methane, ethidium bromide, dimethyl sulphate or benzyl sulphur). Subsequent reduction and burning is carried out using a phase-based compound (such as alpha, ethylene, propylene, acetone or butane) to hydrogenate the miscible metal. In the presence of a substance such as a butterfly hydrogenation, a hydrogenation clock, a triethoxycarbonyl group or an aryl chloride (4), conveniently at a pH of 6-7 and at ambient temperature, or used 135590. Doc -34- 200927115 Hydrogen in the presence of a metal catalyst, for example palladium on carbon at a pressure of 5 bar hydrogen. Methylation can also be used as a reduction at elevated temperatures (eg between 6 Torr and 120 ° C) The reaction is carried out in the presence of formic acid. Subsequent nitro reduction is, for example, hydrogen and a catalyst such as palladium on carbon, platinum dioxide or Raney nickel or using other reducing agents such as iron or rhodium. It is carried out in the presence of an acid such as acetic acid. Subsequent nitration of the imine group followed by reduction to obtain an amylamine-imine compound system (for example) using an alkyl nitrite (such as isoamyl nitrite) to form a quinone nitroso-imide compound The N-nitroso-imine compound is then reduced to the amine-imido compound using, for example, zinc in the presence of an acid such as acetic acid. Subsequent cleavage of the Ch alkoxycarbonyl group to obtain a carboxyl group is carried out, for example, by hydrolysis using an acid such as hydrochloric acid or sulfuric acid or an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. Subsequent guanamine formation is conveniently carried out at a temperature between 〇 and 15 ° C, preferably between 80 ° C, by reacting the corresponding reactive carboxylic acid derivative with the corresponding amine in a solvent or solvent. In a mixture (such as di-methane, dimethylformamide, benzene, toluene, benzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxo), the amine used may also act as a solvent, optionally in the case of a third organic base. Reacting in the presence or in the presence of an inorganic base' or with the corresponding carboxylic acid in the presence of a dehydrating agent (eg in isobutyl methacrylate, sulphur sulfoxide, trimethyl gas decane, phosphorus pentoxide, phosphorus pentoxide, Ν, Νι_dicyclohexylcarbodiimide, n,n'-dicyclohexylcarbodiimide/N_hydroxysuccinimide or hydroxy-benzobisazole) and optionally 4_ Dimethylamino-pyridine, 135590.doc -35- 200927115 N,N'-mono-di-di-β-seat or three-line 0 phenylphosphine/tetra-carbonized carbon should be present by making aromatic compounds appropriate The functional atomic electrophile reaction 'ducts gas, desert or moth atoms onto the aromatic substructure. Suitable gas and indifference electronic reagents can be, for example, Ν-halogen amber quinone imine, H〇cl, η〇Βι>,

(4) Bu〇a, (4) Bu〇Bl·, gas, desert, two deserted cyanuric acid, two gas> odor acid reading, three money or sulphur gas, which can be used alone or with acid (such as hydrochloric acid, hydrogen acid acid) , W fluoroboric acid, trifluoromethanesulfonic acid, sulfuric acid or acetic acid) or Lewis acid (such as iron (111), boron trifluoride hydrate, boron trifluoride etherate or aluminum halide) is used in combination. Other suitable combinations may be cesium ammonium nitrate, KC1 or KBr and 〇xone® or KBr and sodium perborate. Suitable iodine electrophiles can be produced by combining iodine oxidizing agents such as nitric acid, sulfur trioxide, manganese dioxide, cerium 3, hydrogen peroxide, sodium periodate 'peroxide disulfate and Oxone®. Other suitable iodine electrophiles can be, for example, gasified oxime, diiod iodate, and N-iodosuccinimide. These iodine electrophiles can be used in the absence of additives or in the presence of an acid such as acetic acid, trifluoroacetic acid or sulfuric acid or a Lewis acid such as boron trifluoride or copper salt hydrate. If a nitro group is to be introduced, an appropriate nitrophile reagent can be produced, for example, from nitric acid, ethyl acetate, nitric acid, sodium nitrate, N2 hydrazine 5, alkyl nitrate, and tetrafluoroborate nitrate. Some of these agents may be used without additives, but some of them are preferably with acids (such as sulfuric acid or trifluoromethanesulfonic acid, acetic anhydride, trifluoroacetic anhydride), Lewis acids (such as barium triflate). Or iron acetate), p2〇5 or a combination of bases. The S〇3H group can be introduced by reacting an aromatic compound with, for example, concentrated sulfuric acid, S〇3, C1S03H or ClS02NMe2 in combination with indium trifluoromethanesulfonate 135590.doc -36 - 200927115. The deuteration of the aromatic moiety may be carried out by using an individual fluorenyl-based dentate (for example, a vapor) or a thiol anhydride and a Lewis acid (such as _aluminum, _diethylammonium, indium arsenide, diasterium iron). The thiol-electrophile generated by tin (IV), boron trifluoride, titanium (IV) titanium oxide or bromostatic acid (for example, sulfuric acid or trifluoromethanesulfonic acid) is used. The thiol-based system is introduced using the so-called Vilsmeier or Vilsmeier-Haack conditions: dialkyl ketone is combined with carbon helium, sulfoxide, poet or ethanedioxane. The preferred solvent for the electrophilic substitution may vary depending on the electrophile used. The following are some of the more general solvents: di-methane, di-ethane, benzene, di-benzene, ether, fluoro. Hydrocarbon, hexane, quinoline or acetonitrile. The preferred application temperature is in the range of 0 to 180 °C. Subsequent use of nitrous acid or nitrosonium source or equivalent, such as nitrite combined with acid (such as sodium nitrite and hydrochloric acid), tetrafluorodecanoate or alkyl nitrite (such as nitrite nitidine) The ester or isoamyl nitrite) causes the amine group to be gasified to begin replacing the aromatic amine group. The diazotization is _ 1 视 depending on the situation. At a temperature between 〇 and 100 ° C, in dioxane, di-ethane, dimercaptoamine, N-methyl 0, benzophenone, benzene, toluene, gas benzene, tetrazolium Taste, eternal, ethyl acetate, alcohol, ether, dimethoxyethane, dioxin or a mixture thereof (the diazonium of an amine group is detailed, for example, in /«ί. 1976, /5, 251) . Subsequent replacement of the diazo group with a cyano group, a gas or a bromine using cuprous cyanide, cuprous bromide or cuprous bromide, respectively, is referred to as the Sandmeyer reaction (see, for example, March's Advanced Organic Chemistry, Michael B. Smith and Jerry March, John Wiley & Sons Inc., 6th edition, New Jersey, 2007 and cited 135590.doc -37-200927115 used references; the reaction is based on 丨〇. Between 〇 and 12 〇 °c, in a solvent or a mixture thereof. The tetrahydrofolate or acid can be used and heated to 20 to 160 ° C to replace the diazo group with a fluorine atom; this reaction is called a Schiemann reaction. Can be used in 〇 with 12 〇. (At the temperature between: 'It is preferred to use water or an aqueous solvent mixture to treat the diazo compound with an iodide salt (such as sodium hydride) to introduce the gorge. 'Use at a temperature between 〇 and 18 〇. ' The water or aqueous solvent mixture replaces the diazo group with a hydroxyl group. The reaction is usually carried out without other additives, but the addition of cuprous oxide or strong acid® may be advantageous. The base or alkyl group may be between 0 and 120. At the temperature between: via its corresponding disulfide salt or dialkyl disulfide; depending on the type of sulfur used, an inert solvent or aqueous solvent system may be preferred (see, for example, Commw«. 2001) 3' 185 7 and references cited therein. Subsequent substitution of an aromatic amine group with an aryl group can be carried out via a corresponding heavy-weight compound obtainable as described above. With an aryl nucleophile, preferably an aryl group The reaction of acid, ❹ vinegar, trifluoroborate, zinc halide or stannane is carried out in the presence of a transition metal species derived from palladium, rhodium, ruthenium, copper or iron, preferably palladium. The active catalyst can be Transition metals and ligands (such as phosphines, a complex of phosphate, oxazolidine, imidazolidinium, dibenzylideneacetone, allyl or nitrile, transition metal in elemental form (such as palladium/carbon or nanoparticle) or salt (such as gas) a compound, bromide, acetate or trifluoroacetate. In these reactions, the 'diazo compound is preferably in the form of its tetrafluoroborate, between 丨〇.〇 and 180C, preferably 2〇 Under the temperature between i4〇〇c, as the case may be in the second gas, dimethyl carbamide, N-methylpyrrolidone, benzene, benzene, tetra 135590.doc • 38- 200927115

./, a π, soil, % 嗦鼹 gas group is replaced by an aryl group, an alkenyl group, a fast group or a burning green 赵 赵 Du / & 丄 amp &

a smear of nitrile, a transition metal in elemental form (such as palladium/carbon or nanoparticle of iron or palladium) or a salt (such as fluoride ❹)

Difluoromethanesulfonate or trifluoroacetate). The substitution is preferably a difluoro-decanoate, an acid or a phthalate (Suzuki or Suzuki type reaction) of a rare earth or a burnt residue to be introduced, a zinc halide (Negishi or a root bank). Type reaction), stannane (Stille or Still type reaction), decane (Hiyama or Laoshan type reaction), toothed magnesium (Kumada or Kumada type reaction). The terminal alkyne is preferably used in the form of an undisturbed or zinc acetylide derivative. Depending on the electrophilic electron or nucleophilic reaction partner, additives such as halide salts such as lithium hydride, lithium fluoride, tetrabutylammonium fluoride; 1 oxide source such as potassium hydroxide or potassium carbonate; silver salts such as Silver oxide or silver triflate; copper salts such as copper vapor or copper thiophenecarboxylate may be advantageous or even necessary. In the coupling with the terminal alkyne group (s〇nogashira reaeti〇n), cuprous iodide is a preferred additive.偶135590.doc -39- 200927115 The reaction is based on dichloromethane, dimethylformamide, N-roylpyrrolidone, benzene, f benzene, tetrahydrobite, water, ethyl acetate, alcohol , Jun, Dimethyl, Dimethoxy, Diming or a mixture thereof, but depending on the nucleophile, some of them are inappropriate or completely inappropriate. The preferred temperature is -10. 〇 to 180 °c range. Subsequent replacement of an aromatic gas atom, a bromine atom, an iodine atom or an aromatic trifluoro, sulfonyloxy, methoxy or toluene to a hydrogen atom is preferably carried out from palladium, nickel, platinum, Mediated by transition metal species of ruthenium or osmium. As described above, the active catalyst may be a complex of a transition metal and a ligand, a transition metal of the element form or a salt of a transition metal. The Raney nickel or palladium/carbon is the preferred catalyst species. Suitable hydrogen sources may be hydrogen, preferably decane (e.g., dialkoxy decane), borane, hydride (e.g., alkali metal borohydride), formic acid or formate (e.g., ammonium formate). The reaction is preferably at 〇. 〇 and 18〇C 'more preferably 20 ° C to 140 ° C in the chloroform, dimethyl carbamide, monomethyl acetamide, N-methyl pyrrolidone, benzene, toluene, tetrahydrofuran, It is carried out with water, ethyl acetate, alcohol, ether, dimethoxyethane, dioxane or a mixture thereof. Subsequent cyclization of two adjacent heteroatoms is optionally carried out with a carboxy equivalent such as a nitrile, a carboxylic acid vapor or fluoride, a carboxylic acid, a ketene, a carboxylic acid ester or a carboxylic acid thioester. The overall conversion consists of two reaction steps: attaching the carboxy equivalent to one of the two heteroatoms, followed by cyclization with another heteroatom. The first step is the formation of a brewing amine with an amine functional group, which can be carried out as described above. The next reaction step (cyclization with the second hetero atom) can be by acid (eg acetic acid, trifluoroacetic acid, sulfuric acid or hydrochloric acid) or base (eg sodium hydroxide, sodium ethoxide 135590.doc 200927115 or sodium butoxide) In the presence of heating to achieve. Use dehydrating reagents (such as sour livers such as acetic anhydride; orthoesters such as trimethyl orthoformate; sulfite gas; carbon helium; carbon monoxide; tricarbonium chloride; phosphonium; phosphorus pentachloride - a calcined carbodiimide; for example a combination of a triphenylphosphine or a trialkylphosphine phosphine with a diazomonocarboxylic acid dialkyl ester; bromine, iodine or 1,2-dihaloethane, such as hydrazine, 2_ /Smelly PTFE*B) can be beneficial. The reaction is preferably carried out in an inert solvent or mixture (such as di-methane, di-ethane, benzene, toluene, tetrahydrofuran,

The ethers or combinations thereof are carried out, but the cyclization in the presence of an acid or a base can also be carried out in water such as methanol, ethanol, isopropanol or tert-butanol or a solvent of such solvents. The reaction is in hydrazine. 〇 with 2 〇〇. Between the 〇, preferably with 1 button. Perform at a temperature between c. Subsequent cyano reduction to obtain the aminomethyl group is carried out using hydrogen in the presence of a transition metal species or using a hydride. Suitable transition metals can be derived from palladium, nickel, ruthenium, iridium or ruthenium such as palladium/carbon, palladium hydroxide, oxidized or 阮尼锦'. The transition metals can be between the bars, preferably _巴© And between 0 and 18 〇 t:, preferably 20 and 120. (: between the two plants: in a solvent such as ethyl acetate, alcohol (such as methanol or ethanol), two mouths slightly biting the solvent to make succinylamine or & methyl acid or acid. For example, acid (such as Additives of hydrochloric acid, methanesulfonic acid, guaranic acid or acetic acid may be useful for weathering when selected from the salary. Suitable hydride sources may be, for example, borohydrides such as sodium borohydride or borane or Triethylol oxidized cerium lanthanum cerium lanthanum hydride (such as lithium aluminum hydride or hydrogenated monoisobutyl aluminum). These reagents have a combination of disproportionation, such as sodium borohydride. With nickel chloride f gas barrier J can be (for example) tetrahydrogen bite I35590.doc 200927115 urethane, dioxane, 1,2-dimethoxy ethane, dioxane, 12-dichloroethane It is used in the present or toluene; some are also compatible with the alcohol solution. The preferred reaction temperature is in the range of -80 ° C to 160 ° C, more preferably -4 (TC to 60 ° C. Subsequent formation of N- The fluorenyl group can be carried out by treating the cyano compound with an amine. The reaction is preferably carried out in an aqueous or alcoholic solvent at a temperature between 14 and TC. Subsequent formation of the oxadiazole from the N-hydroxyformamyl group is optionally carried out using a carboxy equivalent such as a nitrile, a carboxylic acid vapor or fluoride, a carboxylic acid, a ketene, a carboxylic acid ester or a carboxylic acid thioester. The transformation involves the formation of a ring starting from two adjacent heteroatoms and can be similarly carried out. Subsequent formation of a cyano group from an aminocarbonyl group is optionally carried out using a dehydrating reagent (for example an anhydride such as acetic anhydride, triacetin or trifluoroacetone). Xuan), carbon-burning gas, sulphur sulphur, sulphur dioxide, P 〇Cl3, PCl5, p4 〇 〇, triphenyl phosphite or triphenylphosphine or trialkyl phosphine) combination of four gas methane, hydrazine , 2_dibromotetrafluoroethane or bromine. The reaction is preferably carried out at 0. 温 and 14 (rc between the temperature production Φ under a gas, I2-di-ethane, hexane, ether, two Chewing, benzene, toluene, acetonitrile, mixtures thereof or in the absence of a solvent. Additives such as amines (such as pyridine or triethylamine) or dimethylformamide may be beneficial. ', ', then Adding a carbon nucleophile to a ketone group or a chelating group to obtain a decyl alcohol can use an alkyl or aryl metal compound. The reaction is carried out using lithium or Z. The reaction is preferably carried out at -80. 〇 and 50. (: between hexane, ether, dioxane, tetrahydroanion, dimethoxyethane, benzene, toluene Or it is carried out in:: I35590.doc -42- 200927115 Subsequent reduction of the keto or aldehyde group to obtain the second alcohol or the first alcohol may use a miscible metal hydride (such as sodium borohydride, lithium borohydride, three Ethyl boron hydrogen: lithium 'diisobutylaluminum hydride or lithium aluminum hydride." Reduction can be, for example, mono-methane, 1,2, di-ethane, hexane, ether, dioxane, tetrahydrogen Furose, - mercapto, amine, benzyl, benzene, alpha #, alcohol (eg methanol), water or mixtures thereof, but not all reducing agents are compatible with all such solvents. The preferred temperature is between -80C and 140C, depending on the reducing power of the reagent. Alternatively, hydrogen in the presence of a transition metal catalyst can be used for reduction. ❹ subsequently converting a fluoro group to a tetrazolyl group by reacting cyanide with sodium azide or dimethyl azide, for example, toluene, diphenylbenzene, cyclohexane, dimethylformamide, This is achieved by reaction of dimethylacetamide, hydrazine-methylpyrrolidone, tetrahydrofuran, monooxane, 1,2-dimethoxyethane, alcohol, water or a mixture thereof. The beneficial additives may be ZnBr2, Bu3SnCl, NH4C1.

Bu2Sn〇, A1C13, AlMe3, HNEt3Cl and NEt3. The reaction is preferably carried out at between 20 ° C and 160 ° C. Subsequent nitro reduction is carried out, for example, with hydrogen and a catalyst such as palladium on carbon, platinum dioxide or nickel iridium or using other reducing agents such as iron or zinc in the presence of an acid such as acetic acid. Subsequent formation of the pyrrole ring from the amine group can be, for example, by 2 to 14 Torr. (:, in, for example, acetic acid, water, methanol, ethanol, acetonitrile, hydrazine, 4-dioxane, tetrahydro-11-pentan, toluene, in a Lewis acid (such as acetic acid, p-toluenesulfonic acid or Bi (〇) In the presence of S〇2CF3)), an amine compound is reacted with a succinyl aldehyde or a derivative thereof (for example, 2,5-dimethoxy-tetrahydrofuran or hexane 2,5-dione). 135590.doc - 43- 200927115 Additives such as molecular sieves or other dehydrating reagents such as acetic anhydride may be beneficial. In the reactions described above, any reaction present may be protected by a conventional protecting group which is re-cleaved after the reaction during the reaction. a group such as a trans group, a suspending group, an amine group, an alkylamino group or an imido group. For example, the protecting group of the hydroxyl group may be a trimethyldecyl group, a tert-butyldidecylfluorenyl group, or a trisyl group. Isopropyl decyl, ethyl hydrazino, pentyl, fluorenyl, methyl, ethyl, tert-butyl, allyl, trityl, benzyl yl, 4 gastric methoxy benzyl , tetrahydropyranyl, methoxymethyl, ethoxymethyl or 2-trimethyldecyl ethoxymethyl, the protective group of the ruthenium can be three A methyl group, a methyl group, an ethyl group, a 1,4-butyl group, a propyl group, a benzyl group or a tetrahydro-U group η, a ketone or an aldehyde group may be, for example, derived from decyl alcohol, a ketal or acetal of a diol or a propane-1,3-diol, and a protecting group for an amine group, an alkylamino group or an imine group may be a methyl group, a decyl group, an ethyl fluorenyl group or a trifluoroethylene group. , ethoxycarbonyl, tert-butoxy-carbonyl, oxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl and additionally thiol for the amine group, And the protecting group of the terminal alkyne may be trimethyldecyl, triisopropyldecyl, dibutyldimethyltinyl or 2-perylene-isopropyl. Any mercapto protecting group may be For example) between 〇 and i 2 〇. (between 3, preferably between 丨〇 and 100 ° C, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in an alkali metal test (such as hydrogen) Lithium oxide, sodium hydroxide or lithium hydroxide) in the presence of an aqueous solvent (eg water, isopropanol / water, acetic acid / water, tetrahydrofuran 135590.doc -44 - 200927115 m / water or dip / water) Hydrolyzed cleavage or (for example The aprotic cleavage exists in the presence of ruthenium. The temperature between the three 醯, = methyl 石 HC HC is preferably treated by using a solvent such as hydrochloric acid in a solvent such as acetic acid. Acid treatment, or in the case of 〇 and 8 〇. (:, 盟 / /, according to the situation in an additional solvent such as tetra-furfuran or methanol. Qi] in the treatment of sodium bismuth oxide solution cracked Any of the reduced or reduced protecting groups used may, for example, be in the presence of an acid (n-acetic acid, hydrazine hydrochloride or sulfuric acid) at a temperature between I and 10 In aqueous solvents, for example, water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or hydrolyzed cleavage in dip / water, or, for example, aprotic in the presence of iodotrimethyl decane Lysis. The trimethylsulfanyl group is, for example, cleaved in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide in water, an aqueous solvent mixture or an alcohol such as methanol or ethanol. Acids such as hydrochloric acid, trifluoroacetic acid or acetic acid may also be suitable. Cracking pass

It usually occurs at relatively low temperatures (for example between _6〇 and 6〇°c). The decyl group other than trimethyl ruthenium--T-based decyl group is preferably cleaved in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid at a temperature between it and the loot. A particularly suitable decyl cleavage method is based on an organic solvent at temperatures between -20 and 1 〇〇 ° C (such as sigma, tetrahydro oxime, dioxin, dimethoxy ethene, benzene) Fluoride salts (for example, tetrabutylammonium fluoride, hydrogen fluoride or potassium fluoride) are used in benzene, dichloroethane or dioxane. The benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously in the oxime and in the oxime. Between (:: preferably between 20 and 60 ° C and at a pressure of 1 to 7 bar, preferably 3 to 5 bar I35590.doc -45 - 200927115, in a solvent such as methanol, ethanol, In ethyl acetate or glacial acetic acid, hydrogen hydrolyzed cleavage of β in the presence of an acid such as hydrochloric acid, for example, in the presence of a reagent such as hydrazine/carbon, palladium hydroxide or platinum oxide, in a clarifying agent such as benzene Dimethyl decyl iodide, boron trioxide or boron trifluoride in the presence of decyl ether, thioanisole or pentadecyl benzene may also be used together with a benzyl ether derivative. Polyelectron benzyl residue (such as a decyloxybenzyl group) may also be used at a temperature between 10 and 120 c, preferably in an alcoholic or aqueous solvent (for example) 2,3-one gas-5,6-dicyano! Oxidative cleavage of 4-phenylhydrazine (DDQ) or ammonium cerium nitrate (CAN). The 2,4-dimethoxybenzyl group is preferably decomposed in trifluoroacetic acid in the presence of a scavenger such as benzophenone. Butyl or a second butoxycarbonyl group is preferably used by using a solvent such as dichloromethane, dioxin, methanol, isopropyl hydrazine, water or ethyl (4) with an acid such as trifluoroethane. Treatment with acid, sulfuric acid or hydrochloric acid or iodine trimethyl decane for cleavage.

The methyl group of the third amine can be cleaved by treatment with 1-oxyethyl phthalate. Hydrogen acid and boron tribromide are particularly suitable for the cracking of methyl ether. The compound of formula 1 can be resolved into its enantiomers and/or diastereomers as described above. Thus, for example, the cis/trans mixture can be resolved to its cis-anti-isomer and the racemic compound can be separated into its enantiomer. The cis/reverse mixture can be resolved, for example, by chromatography to its cis-trans isomer. The existence of the form of the elimination of the foreign party! The compound can be obtained by a method known per se (see Allinger NL and Eliel EL "τ〇ρ&& Stereochemistry- - ^ Wiley Interscience, 1971)^^ as its optical enantiomer and diastereomeric of the psychedelic compound The mixture of structures can be resolved by its own known methods (such as chromatography and/or fractional crystallization) by utilizing its different physicochemical properties to its diastereomers; if the compound obtained thereafter is external The racemate can be resolved to the enantiomer as described above. The racemate is preferably formed by column chromatography or by crystallization from an optically active solvent or by formation of a salt or derivative with an optically active substance (which forms a salt or a derivative with a racemic compound). )) The reaction is resolved. Salts can be formed using enantiomerically pure acids (for basic compounds) and using enantiomerically pure bases (for acidic chelates). Diastereomeric derivatives are formed using enantiomerically pure adjuvant compounds such as acids, reactive derivatives or alcohols thereof. Separation of the diastereomeric mixture of the salt or derivative thus obtained can be achieved by utilizing its different physicochemical properties (e.g., solubility differences); it can be derived from a pure diastereomeric salt by the action of a suitable reagent. Or the derivative releases the free enantiomer. The optically active acids commonly used for this purpose are, for example, tartaric acid in the form of 0 and L, dibenzyl bromide/pyridic acid-o-methyl-based tartaric acid, rhythmic acid, mandelic acid, camphoric acid, face acid, Aspartic acid or quinic acid. The optically active alcohol which is suitable as an auxiliary agent may be, for example, (+) or (-)·methanol and the optically active thiol group in the guanamine may be, for example, (+)· or (·)-fluorenyloxycarbonyl. As described above, the compound of formula I can be converted to a salt using an inorganic or organic acid, especially for medical purposes, to a physiologically acceptable salt, with the proviso that compound 1 has a basic residue. Acids which can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, decanesulfonic acid, phosphoric acid 'fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. If the compound of formula I contains an acidic residue, such as, for example, a carboxy group, it can be converted to its salt using no base or organic base of I35590.doc-47-200927115, especially for medical purposes to be physiologically acceptable. Salt. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium isopropoxide, magnesium hydroxide, magnesium ethoxide, ammonium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine. , N-methyl-D-glucosamine, L-lysine, L_arginine and piperazine. [Embodiment] Unless otherwise specified, groups, residues and substituents, in particular. To R14, L, X, m, n and 0 are as defined above and below. If a residue, a substituent or a group appears several times in a compound, it may have the same or different meaning. Some preferred meanings of the individual architectural compounds, groups and substituents of the compounds of the invention are given below. A first aspect of the invention is a first subgeneric embodiment of the invention

❹ wherein the bicyclic core structure of formula 1.1 is substituted by R" to rM, and wherein R to R\R" to R14 are as defined above and below (except for the compounds contained in formulas ΙΙ to 8.8) 'its tautomers, their stereoisomers' and mixtures thereof and salts thereof. A second subclass of the invention is directed to a compound of formula 12 135590.doc -48 - 200927115

R R

1.2 wherein the bicyclic core structure of the formula Ι·2 is optionally substituted by r" to Ri4, and wherein R1 to R3 and R11 to R14 are as defined above and below, the tautomer thereof is a stereoisomer thereof, Mixtures and their salts. A third subclass of the invention is directed to a compound of formula 13 〇

The double-ring core structure of the formula 1.3 is optionally substituted by R11, and wherein R1 to R3 and the ruler ^ to! ^4 is a tautomer as defined above and below, a stereoisomer thereof, a mixture thereof and a salt thereof. A fourth subclass of the invention is directed to a compound of formula 1.4, 4.4 0 R1 wherein the bicyclic core structure of formula 1.4 is optionally substituted with r1 1 to r1 * and wherein R to 11 and size 11 to R14 is a tautomer thereof as defined above and below, its stereoisomers, mixtures thereof and salts thereof.

The room of the present invention is a compound of the formula R2x> 〆\R1 1.5 135590.doc -49- 200927115 wherein the bicyclic core structure of the formula Ι·5 is optionally subjected to r11 Substituting to r14 and wherein R to R and the ruthenium to Rl4 are as defined above and below (both compounds of II.7 and Π.8), and the tautomers thereof are stereoisomers thereof, Mixtures and their salts. A sixth subclass of the invention is directed to a compound of the formula 66

1.6 Ο wherein the bicyclic core structure of formula 1,6 is optionally substituted by Rn to R14, and wherein R1 to R3 and R^Rl4 are tautomers as defined above and below, stereoisomers thereof, mixtures thereof And its salt. A seventh subclass of the invention is directed to a compound of formula 1.7

Wherein the bicyclic core structure of formula 1,7 is optionally substituted with Rn to Ri4, and wherein R1 to R3 and R1 to R14 are as defined above and below (while excluding compounds encompassed by formula II.3), Isomers, stereoisomers thereof, mixtures thereof and salts thereof. An eighth subclass of the invention is directed to a compound of formula 18

Wherein the bicyclic core structure of formula 1.8 is optionally substituted by Ri 1 and 135590.doc • 50· 200927115, wherein tR1 to R3 and R" to r 4 are as defined above and below, the tautomer thereof Stereoisomers, mixtures thereof and salts thereof. A ninth subclass of the invention is directed to a compound of formula 19

Wherein the bicyclic core structure of formula 1.9 is optionally substituted with Ri 1 to Ri 4 , and wherein Ri to R 3 and R" to R are as defined above and below, the tautomeric 〇 ' '''''' Mixtures and salts thereof. The tenth subclass of the invention is directed to a compound of the formula L0

Wherein the bicyclic core structure of the formula Ι·10 is optionally substituted by Rn, and wherein R to R3 and R11 are as defined above and below, their stereoisomers, stereoisomers thereof, mixtures thereof and salts thereof. Preferred compounds of the invention are those of the formula j^ to 1〇, wherein R represents an aryl or heteroaryl group, and aryl means phenyl or naphthyl, and heteroaryl means pyrrolyl, Furanyl, thienyl, pyridyl, fluorenyl, benzofuranyl, benzothienyl, quinolyl, isoquinolinyl, or D-l- yl, furyl, thienyl, pyridyl, wherein 1 or 2 ch replaced by N 'or thiol, benzofuranyl, benzothienyl, quinolyl, isoquinoline 135590.doc -51 · 200927115 base 'where 1 or 2 CH is replaced by N, or 1 Side oxy-dioxanyl, 2,3-dihydroindolyl, 2,3-dihydro-2-indolyl-based, 2,3-dibenzobenzo-indolyl, 2,3·Dihydro-2-oxooxy-1 Han-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl, benzo[1,3]·di Oxecyclopentyl, 〗 〖2-dihydro-2-oxoquinolinyl, 1'4-dihydro-4-inoxy-quinolinyl, diar-arc-oxy-isophthalene Base, 1, 2_ one wind-2-side oxy group 啥 啥 琳 基 base, 1, 'dihydro _ 4- side

❹ oxy-oxazolidinyl, anthracene, 2-dihydro-2-oxoquinoxaline or 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl, wherein The aromatic ring and the heteroaryl ring are independently substituted by one r4, one to four identical or different R5 and one R6. Preferably, R represents a phenyl group, a aryl group, a biting group, a specific β group, a pyridyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a fluorenyl group, a benzopyrylene group. °Sitting, benzotriazine, benzoxanthyl, benzoindolyl, quinolinyl, isoquinolinyl, quinazolinyl, acridinyl, quinoxalinyl, 2, 3-diaza-oxy-indenyl or 1,2,3,4-tetrahydro-3-o-oxo-quinoxalinyl' wherein any of these groups are independently passed through an R4, one to four The same or different R5 and one R6 are substituted. More preferably, 'R} represents phenyl, naphthyl, β-pyrrolyl, beta-bite, gnabyl, naphthyl, benzofuranyl, fluorenyl, benzothienyl, benzomethanyl ° sit-based, benzotrienyl, benzo-oxo-β, benzoindole, sulfonyl, isoquinolyl, quinazolinyl, acridinyl, quinoxalinyl, 2, 3_Diazin-2-yloxy-indenyl or tetrahydro-3-yloxy-quinoxalinyl, wherein any of these groups are independently independent of one R4 and one to four or 135590.doc -52· 200927115 Replaced by the same R5. Most preferably, 'R1' represents phenyl, "bisazolyl. Pyridyl, benzofuranyl, fluorenyl, benzimidazolyl, oxazolyl, benzotriazolyl, benzothiazolyl, 2,3-dihydro-2-oxo-indenyl or 1,2,3,4-Tetrahydro-3-o-oxo-quinoline, wherein any such groups are optionally substituted independently by one r4 and one to four different or identical R5. Particularly preferred are 4-aminomethylindenyl-phenyl, 4-(morpholin-4-ylmethyl)phenyl, 4-amino-phenyl, 4-hydroxyphenyl, 4-amino-3- Fluoro-phenyl, 4-amino-3-© gas-phenyl, 4-amino-3,5-dioxa·phenyl, indol-3-yl, 吲哚_5-yl, 吲哚- 6-yl, benzimidazole _5-yl, carbazole _5-yl, benzothiazole _5-yl and benzoindole-6-yl. R and R together with the double bond to which they are attached represent a benzo ring or a timid ring. Both are independently substituted by R7, ... and ruthenium 9, or fenfuran, pyrrole, pyridazine, Pyrimidine or pyrazino ring, wherein any of these groups are independently substituted by the order of ... and 8 or ... and 9 or the oxime, oxazole, oxazole, thiazole, and dysentery Any group of oxazolo or isoindole and '% of the towel' is optionally substituted by R7. Preferably, R and R together with the double bond to which they are attached represent a benzo ring or a ratio of a bite to a ring, both of which are independently substituted by r7, r8 & r9, or 胄#胄azine, mouth biting and Or a pyridazine ring, wherein any such earthy group is independently substituted by R7 and R8 or R8 and RV, or by a ring or a meditative ring, both of which are optionally substituted by r7. The 9RW, together with the double bond to which it is attached, represents a benzo ring or a K ring which is independently substituted by m9, or represents a separate 135590.doc -53- 200927115 by R7 and R8 or R8 and R9. A pyrrole ring, especially a benzo ring substituted independently with R7, R8 and R9, as appropriate. R4 represents fluorine, gas, bromine, C!-4, based, transalkyl, Ci-4 alkoxy nitro, amine, C丨_3 alkylamino, bis(Cw alkyl)amine, pyrrole Pyridin-1-yl, 2-oxooxypyrrolidin-1-yl, piperidin-1-yl, 2-oxo-slightly-l-yl, oxa-4-yl, 3-side Base-? scary-based, slightly π-methyl-1-yl, 2-oxooxyl-l-yl-1-yl, 3-oxooxy-indenyl-1-yl, 3-alkyl)-piperazine-1 -yl, 4-((^.4 alkylcarbonyl)-piperazine-oxime 1-yl, 4-(C3-6cycloalkyl)-[beta]-l-yl, 4-(Ci-4 Oxycarbonylcarbonyl)-piperazin-1-yl, 4-(C丨-4alkylsulfonyl)-piperazin-1-yl, 2-oxo-4-(Ci-3 alkyl)-β Bottom-β-l-yl, 3-oxo-oxy-4-(C!.3^-yl)-Break 11 Qin-1-yl,

Cw alkyl carbonylamino, (hetero)arylcarbonylamino, (hetero)aryl-Ci-3alkyl-arylamino, Ci_3 oxime-decarbylamino, aminylamine , Cw alkyl-aminocarbonylamino, bis(C!.3 alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamine, Morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino, 4-(Ci_3 alkyl)-® base-1-yl-pylamino, C!.3 alkyl- Alkylamino, (hetero)arylsulfonylamino, (hetero)aryl-Cw alkyl-sulfonylamino, alkylalkyl-carbonylamino, NKCw alkyl)-(hetero) Arylcarbonylamino group, >^((^-3 alkyl)-(hetero)aryl-Cw alkyl-carbonylamino group, alkyl alkoxy-carbonylamino group, N·(aminocarbonyl)- C, .3 alkylamino, NYCh alkyl-aminocarbonyl)-C, _3 alkane 135590.doc • 54- 200927115 arylamino, N-[di(Cl_3 alkyl)aminocarbonyl]_Cl-3 Amino group, N-CCw alkyl)-(:, .3 alkyl-sulfonylamino group, N-(C].3 alkyl)-(hetero)arylsulfonylamino group, N_(Cl -3 alkyl)_(hetero)aryl·(^^alkyl-sulfonylamino group, pendant oxy-merine _1_yl, 2,4-di-oxy-m-"Shenry-1-yl, 2,5-di-oxy-imidazolidin-1-yl, 2-sided oxy-hexahydropyrimidin-1 - a base wherein the nitrogen atom at position 3 of the above group is optionally substituted by a methyl group, cyano, carboxy, C, .3 alkoxy-alkyl, aminocarbonyl, C..3 alkyl-amino Carbonyl, bis(C^alkyl)-aminocarbonyl, oxarrolidin-1-yl·yl, 2-(decyloxymethyl)^pyrrolidinyl-yl-carbonyl, 3-(methoxy Methyl)_°pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, morpholin-4-yl, oxime-_1-yl-yl, 4-(Ci_3) ·Break D-methyl-yl, (hetero)arylaminocarbonyl, alkyl)-(hetero)arylaminocarbyl, (hetero)aryl_Cl_3 alkylaminocarbonyl, N-CCw Alkyl)-(hetero)aryl-CN3alkylaminocarbonyl, ❹Cl-3alkyl-based, (hetero)aryl-rebel, carboxy-Cw alkyl, Cw alkoxy-carbonyl-Cw Alkyl, cyano-C!.3 alkyl, aminocarbonyl-Cw alkyl, Cw alkyl-aminocarbonyl-C!.3 alkyl, bis((:丨3 alkyl)-aminocarbonyl -Ci-3 alkyl, pyrrolidin-1-yl-carbonyl-Ci_3 alkyl, piperidin-1-yl-carbonyl-Cu , morpholin-4-ylcarbonyl-Cw alkyl, piperazin-1-yl-carbonyl-Cw alkyl, 4-(Ci-3 alkyl)-slightly 嘻_1_yl-yl-Ci_3 Base, stilbene-oxime 1_3 alkoxy, Ci-3 alkoxy _ benzyl-Ci-3 alkoxy, chaotic 135590.doc •55· 200927115 ke-C!·3 alkoxy, aminocarbonyl _ Cl_3 alkoxy, Cl.3 alkyl-aminocarbonyl-C!-3 alkoxy, bis(CN3 alkyl)-aminocarbonyl-CN3 alkoxy, oxarrolidin-1-yl-carbonyl-Cw Alkyl-oxyl, piperidin-1-yl-carbonyl-C 1 ·3 alkoxy, morphine-4-yl-aryl-C 1.3 alkyl-lactyl, oxazin-1-yl-carbonyl- Cw alkoxy, '(Cw alkyl)-piperazin-1-yl-carbonyl-Ci-3 alkoxy, via ruthenium 1.3, ruthenium 1.3 alkoxy _ 匚 1_3 alkyl, amine - 〇1-3 alkyl, Ci_3 alkylamino-Ci-3 alkyl, bis(Ci_3 alkyl)-amino-C!-3 Q alkyl, ° ratio bite-1-yl-Ci-3 Base, 2-sided oxocarboline-1-yl-

Ci-3 yard base, brigade bite __ base _Ci.3 dazzle 1 base, 2 - side oxy-buck bite - l-base-Ci-3 base, ahla-4 base-Ci-3 dazzle , (indolyl-morphin-4-yl)-Ci-3 alkyl, (dimethyl-morpholin-4-yl)-(:].3 alkyl, 3-sided oxy-morpholine- 4-based-C 1 -3 alkyl, slightly ～ 1 -yl-C 1 -3 alkyl, 2-tertiary oxy-branched 0-methyl-Cw alkyl, 3-sided oxy- Piperazine-1-yl-Cw alkyl, 4-(C丨-3 alkyl)-piperazin-1-yl-Ci-3 alkyl, 2-sided oxy-'(Cualkyl)-piper Qin-1-yl-oxime 1.3 alkyl, 3-sided oxy-4-(〇1_3 alkyl)-tand-1-yl-•C-bu-alkyl,

Cw alkylcarbonylamino-Cw alkyl, (hetero)arylcarbonylamino-Cw, benzyl group, thio-Ci-3, oxygenate Base, Ci_3 alkylthio-Ci-3 alkoxy, Cl-3 alkyl, aryl-Ci-3 alkoxy, Ci_3 alkylsulfonyl-Cw alkoxy, amine-C!_3 Alkoxy, Cw alkylamino-Cw alkoxy, di(c)-3-alkyl)-aminoalkoxy, oxime-1_yl-Ci_3 alkoxy, 2-sided oxybipro 1-2-1-yl-135590.doc -56- 200927115 CN3 alkoxy, piperidin-1-yl-Cw alkoxy, 2-oxooxypiperidin-1-yl-Ci-3 alkoxy, _琳-4-基-C!-3 烧气基,3_侧氧_ _ ^^-4 -yl-Ci-3 alkoxy, brigade 11 Qin-1-yl-C〗.3 Base, 2-oxo-piperazin-1-yl-Cw alkoxy, 3-o-oxy-piperazin-1-yl-Ci·3 alkoxy, 4-((1!1_3 alkyl) -azizin-1-yl-oxime 1-3 **oxy, 2-o-oxo-4-((^-3 alkyl)-piperazin-1-yl-Cw alkoxy, 3-side oxygen 4-(Ci.3 alkyl)-piperazin-1-yl-d.3 alkoxy, C|-3 alkylthio, Ci-3 alkyl sulfonyl 'Cl·3 alkyl Renewed ❹ 、, (hetero) aryl continuation base, amine sulfhydryl group, C!. 3 alkyl-amine based tank Sulfhydryl, bis(Cl-3 alkyl)_amino group thiol group, η ratio slightly bite-1_yl-continuation base, pie bite-1-base-calcinyl base, holly-4-yl-continuation Stuffed base, ti base _1_ base-continuous brewing base, 4-(Ci.3 succinyl)-benzin-1-yl-yield base, difluorodecyl, trifluoromethyl, difluoroantimony , trifluoromethoxy, 2,2,2-trifluoro-1·hydroxyethyl, 2,2,2-trifluoro-buhydroxy·ι_methylethyl, 2,2,2-trifluoro 1-hydroxy-1-(trifluoromethyl)ethyl, ® c3.6 cycloalkyl, c3_6 cycloalkoxy, c36 cycloalkyl-Cw alkyl, C3-6 cycloalkyl-Ci-3 -oxy, (hetero)aryl, (hetero)aryloxy, (hetero)aryl-C13 decyl, (hetero)aryl-Cw alkoxy, (hetero)aryloxy-Ci3 alkyl, Or tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-indenyl, tetrahydropyran-4-yl-oxy, tetrahydrofuranyl-c alkoxy, tetrachloropyranyl- Ci-3 alkoxy, wherein the above (hetero)aryl group is phenyl, naphthyl or 135590.doc • 57· 200927115 ° pyryl, furyl, thienyl, "pyridyl, fluorenyl, benzene And β-Fanyl, benzo <» thiophene, indolinyl, isoindolyl, or pyrrole a group, a furyl group, a thienyl group, a pyridyl group wherein 1 or 2 CHs are replaced by hydrazine, or a fluorenyl group, a benzofuranyl group, a benzothienyl group, a quinolyl group, an isoquinolyl group, of which 1 to 3 CH is replaced by hydrazine, or 1,2-dihydro-2-oxooxypyridyl, 1,4-dihydro-4-yloxy-pyridyl, 2,3-dihydro-3-oxo A thiol-indenyl group, a 1,2,3,6-tetrahydro-3,6--one-oxy-indenyl group, a 1,2-dihydro-2-oxo-oxy group. Stationary, 3, cardinyl dihydro-4-oxo-pyrimidinyl, tetrahydro-2,4 di-oxy-pyrimidinyl, 1,2-dihydro-2-iso-oxy-β-pyrazine, ^ , 'tetrahydro-2.3-di-oxy-pyrazinyl, 2,3-dihydro-2-oxo-indenyl, 2.3-dihydrobenzofuranyl, 2,3-dihydro- 2_sideoxy·17/_benzimidazolyl, 2,3-dihydro-2-oxooxybenzoxazolyl, anthracene; dihydro-2-_2 oxo-quinolinyl, 1 ,4-dihydro·4_sideoxy·quinoline, 12-dihydro-1-oxooxy-isoquinolyl, anthracene, 4-dihydro-4-yloxy-porphyrinyl, 1 , 2-dihydro-2-oxo-quinazolinyl, Μ_dihydro-4, pendant oxy-quinazolinyl, 1,2,3,4-tetrahydro-2,4-di Oxy-quinazolinyl, anthracene, 2_monohydro-2-oxoquinoxalinyl, ns〆-tetrahydro_3_sideoxy-quinoxalinyl, 1,2,3,4-tetra Hydrogen-2,3-di-oxyl-quinoxalinyl, anthracene, 2-dihydro-1-oxo-pyridazinyl, 1,2,3,4-tetrahydro-ι, 4-two-sided Oxy-pyridazinyl, acridinyl, coumarinyl, 2,3-dihydro-benzo[indenyl]dioxanyl or 3,4-dihydro-3-indolylbenzo [丨(4)oxazinyl], and 135590.doc • 58 - 200927115 where Any of the groups described in the (hetero)aryl group may be optionally substituted by one or two R10 which may be the same or different, preferably 'R4 represents fluorine, chlorine, bromine, C.-4 alkyl, hydroxy, Cl_4 alkane. Oxyl group, amine group, Cl.3 alkylamino group, bis(Ci_3 leu) amine group, η 洛 咬 - base, 2-sided oxy-pyrrolidin-1-yl, piperidin-1-yl 2, side oxygen - ° Chen. -1 -yl, phenanthyl-4-yl, 3-sided oxy-Nylide-4, phenyl, "桊-h, 2-sided oxy-piperazin-1-yl, 3- Oxyl-piperazin-1-yl, 4-(Ci.3 alkyl)-piperazin-1-yl, 4-((^.4 alkylcarbonyl)-piperazin-1-yl, '( Ο3 —cycloalkylcarbonyl)-piperazin-1-yl, 4-((^.4 alkoxycarbonyl)-pyrazine-1-yl, 4-(0^4 alkylsulfonyl)-piperazine -1-yl, 2-sided oxy-'(Cw alkyl)-piperazin-1-yl, 3-o-oxo-4-((:, .3 alkyl)-piperazin-1-yl, C--3 alkyl-carbonylamino, (hetero)arylcarbonylamino, (hetero)aryl-Cw alkyl-carbonylamino, Ch alkoxy-carbonylamino, aminocarbonylamino, Cl _3 alkyl-amino-based amino group, bis(Cl-3alkyl)aminocarbamino group, ratio 11 each 1-yl-amino-amino group, Nichinin-1-yl-rebel Amino, morphine-4-yl-andylamino, brityl 11-methyl-1-yl-arylamino 4-(Ci.3 alkyl)-piperazin-1-yl-carbonylamino, cyanide Base, carboxyl group, C..3 alkoxy-carbonyl, aminocarbonyl, Cw alkylaminocarbonyl, bis(Cw alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl, 2-(A Oxymethyl)-«byrrolidin-1-yl-carbonyl , 3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, morpholine-4-yl-yl-yl, cyano-1-yl-yl , 4-(Ci-3 alkyl)-slightly '-I-yl-several 135590.doc -59- 200927115 base, n-(cN3 alkyl)-(hetero)arylaminocarbonyl, N-CCw -(hetero)aryl-Cw alkylaminocarbonyl, C 1-3 alkyl-hexyl, (hetero)aryl-yl, hydroxy-Cw alkyl, Cw alkoxy-Cw alkyl, Amino-Cw alkyl, Ci-3 alkylamino-Cw leucoyl, bis(Cw alkyl)-amino-Ci-3 alkyl, pyrrolidin-1-yl-Cu alkyl, 2-sided oxygen Benzyl-pyrrolidin-1-yl-C!-3 alkyl, chloro-4-yl-Ci-3, (methyl-nor--4-yl)-Ci-3 Methyl-?啦_ 4 -yl)-C1 -3 alkyl, 3 ·sideoxy-Lip _ 4-base-Ci_3 Hyun!

Ci_3 alkylamino-Ci.3 alkyl, (hetero)arylalkylamino-C!-3 alkyl, hydroxy-C, .3 alkoxy, CN3 alkoxy-Cw alkoxy , trifluoromethyl, difluoromethoxy, trifluoromethoxy, 2,2,2·trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-hydroxy-1-indolyl Ethyl, 2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, (hetero)aryl, (hetero)aryl-C!.3 alkyl or (hetero)aryl Oxyl, wherein the above (hetero) 3⁄4• group is phenyl, decyl, n-l- yl, β-follow, thienyl, pyridyl, fluorenyl, benzofuranyl, benzothiophene, quinoline And isoquinolyl or pyrrolyl, furyl, thienyl or pyridyl, wherein hydrazine or two CH are replaced by hydrazine, or fluorenyl, benzofuranyl, benzothienyl, quinolinyl or isoquino A phenyl group in which 1 to 3 CHs are replaced by hydrazine, and wherein the above (hetero)aryl group is optionally substituted by R10. More preferably, R4 represents fluorine, gas, Cw alkyl, hydroxy, c..4 alkoxy, amine, Cl.3, and amine (Ci_3 alkyl) amine. , Π 略 -1-yl, piperidin-1-yl, morpholin-4-yl, C -3-alkyl-carbonylamino, aminocarbonyl, Cw alkyl-aminocarbonyl, bis (cN3 Alkyl)-aminocarbonyl, (N-methyl)-benzylaminocarbonyl, (N-methyl)-phenylaminocarbonyl, ° ratio 0--1-yl-rebel, 2-( Methoxyindenyl)-indolepyrrole b-l-yl-carbonyl, 3-(methoxymethyl)-pyrrolidinyl-carbonyl, piperidinyl-yl-carbonyl, morpholin-4-yl -carbonyl, hydroxy-c,.3 alkyl, Cw alkoxy-oxime Cl-3 succinyl, amine-Cw alkyl, Cw alkylamino-Ci-3 alkyl, one (Ci_3 alkyl)- Amino-Ci.3, morphine-4-yl-Ci.3 alkyl, (2-methyl-morpholin-4-yl)-(:.3 alkyl, (2,6·2) Methyl-morpholin-4-yl)-C _3 alkyl, 3-sided oxy-morpholine-4-yl-methyl, pyrrolidine-l-yl-Cw alkyl, 2-sided oxy- Pyrrrolidine-fluorenyl-yl-3-alkyl, Cl_3 alkylcarbonylamino-c]·3 alkyl, phenylcarbonylamine*_Cl3 alkyl, imidazolyl-C丨3 alkyl, triazolyl-C丨_3 alkyl, trifluoromethyl, difluorodecyloxy, trifluoromethoxy, 2,2,2-trifluoro_1-hydroxyethyl, 2,2 , 2-trifluorofluoro-1-hydroxy-1-methylethyl or 2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl. Most preferably, R4 represents fluorine, Gas, methyl, hydroxy, methoxy, methylamino, morpholin-4, ethionylamino, aminocarbonyl, methylpropylaminocarbonyl, (Ν-methyl)-benzyl Aminocarbonyl, (Ν-methyl)-phenylamino, dimethylamino-carbonyl, diethylaminocarbonyl, piperidin-1-ylcarbonyl, morpholine-4-ylcarbonyl, pyrrole啶_丨_yl-carbonyl, 2-(decyloxyindenyl)-pyrrolidinyl-hydrazinyl-carbonyl, hydrazine-hydroxy-ethyl 135590.doc -61 - 200927115, 1-hydroxy-1-methyl- Ethyl, 2,2,2-trifluoro-1-hydroxymethyl-ethyl, ethyl hydrazinyl fluorenyl, phenylcarbonylamino fluorenyl, 2_sideoxyl than slightly -1-yl- Methyl, oxime-4-yl-methyl, 3-oxo-oxy-l-yl-methyl-methyl, imindol-1-ylindenyl, tris-s-yl-methyl or (2_ 曱Benzyl-4-yl)-methyl. R5 and R6 are independently selected from the group consisting of fluorine, gas, bromine, and Ci.3 alkyl. C: 2·3 alkynyl, trimethyl fluorenyl, thiol, Ci·3 aerated group and murine group are preferably selected from the group consisting of nitrogen, fluorine, gas, methyl, ethyl, ethynyl, trifluoromethyl, The hydroxy group, the methoxy group and the ethoxy group are more preferably selected from the group consisting of hydrogen, fluorine, gas, mercapto, ethynyl, hydroxy and decyloxy. If R5 and R6 are bonded to adjacent carbon atoms, they may be additionally represented together. Methyleneoxy, monofluoromethyleneoxy, ethyldioxy or C3-5 alkyl, preferably methylenedioxy, ethyl-1,2-dioxo The group, the propyl group or the butyl group is more preferably a methylene group or a oxy group or an ethyl group, a 1,2-dioxy group, and preferably an ethyl-1,2-dioxy group. Preferably, R7 represents fluorine, chlorine, C]_4, a base group, a C group, a 4-oxooxy group, a nitro group, an amine group, a Ci-3 alkylamino group, and a di(C丨-3 alkyl group). Amino, indole-1-yl, 2-oxo-oxyl-l-yl-1-yl, succinyl-1-yl, 2-oxooxy-Ben, base, stimuli, _4-based, 3 - pendant oxy-morphin-4-yl, 3-oxo-piperazin-1-yl, 4-(Ci_4 alkylcarbonyl)-piperazin-1-yl, Cw alkyl-carbonylamino, Hetero)aryl-carbonylamino, CN3 alkoxy-arylamino, Ci_3 alkyl-aminomethylamino, bis(Ci_3)ylaminocarbonylamino, pyrrolidin-1-yl-carbonyl Amino, piperidin-1-yl-arylamino, oxime '-4-yl-arylamino, Cl-3 alkyl- aryl 135590.doc -62- 200927115 base, c!_3 Alkylamino-sulfonylamino group, bis(c^alkyl)amino-sulfonylamino group, phloindole-1-yl-hydroxylamino group, ketone-1-yl-term Mercaptoamine, morpholin-4-yl-sulfonylamino, (hetero)arylsulfonylamino, Ν-γ decyl hCu alkyl-carbonylamino, N-CCualkyl)-( Hetero)arylcarbonylamino,alkyl)-C-]3 alkoxy-carbonylamino, N-CCw alkyl-amine Carbonyl)-Cw alkylamino, ^[-[diyl]alkylcarbonyl]-<^_3 alkylamino, NJCw alkyl hCu alkyl sulfonyl-sulfonylamino, alkyl )-(hetero)arylsulfonylamino-cyano, (hydroxyimino)aminomethyl, (Cl-3 alkoxyimino)aminomethyl, carboxyl, C, .3 alkane An oxy-carbonyl group, an aminocarbonyl group, a Ci-3 alkyl-aminocarbonyl group, a bis(Ci_3 alkyl)-aminocarbonyl group, a pyrrolidin-1-yl group, a thiol-l-yl group, Scared _4 - base - several bases

Cw alkyl-carbonyl, (hetero)aryl-carbonyl, carboxy-Cw alkyl, Ci.3 alkoxy-carbonyl-Cw alkyl, cyano-C!.3 alkyl, aminocarbonyl-Ci.3 Alkyl, Cw alkyl-aminocarbonyl-® CN3 alkyl, bis(Ci-3 alkyl)-aminocarbonyl-Cw alkyl, pyrrolidin-1-yl-yl-C 1-3 alkyl, °Bottom-I-yl-aryl-Cl-3 alkyl, holly-4-yl-mono-C1 -3 leuco' carboxy-Cw alkoxy, Cw alkoxy-carbonyl-Cw alkoxy , cyano-Cw alkoxy, aminocarbonyl-Cw alkoxy, C!-3 alkyl-aminocarbonyl-Cw alkoxy, bis(CN3 alkyl)-aminocarbonyl-Cw alkoxy, Pyrrolidin-1-yl-carbonyl-Cw alkyl-oxy, piperidin-1-ylcarbonyl-Cw alkoxy, morpholin-4-yl-carbonyl-C!.3 alkyl-oxy' 135590 .doc -63· 200927115 基基匚1-3H*, 匚1.3 alkoxy-(^1-3 alkyl, amine-^!1-3 alkyl, Cl-3 alkylamino _ Ci.3 alkyl, di(Ci_3 alkyl)-amino-Ci-3 alkyl, p-Bile-1-yl-Ci.3, 2-o-oxy-n ratio基-Ci_3 alkyl, Ci-4, alkyl-amino-Ci-3, N-(Ci_3H)-Ci-4 alkylamino-Ci-3, 2 - Side oxy-pyro -1-yl-Cualkyl, 3-o-oxo-morpholin-4-yl-Cw alkyl, hydroxy-Cw alkoxy, Cw alkoxy-CN3 alkoxy, Cw alkylsulfinyl -Cw alkoxy, Cw alkylsulfonyl-Cw alkoxycarbonyl, bis(Ci.3 alkyl)-amino-C丨_3 alkoxy, 2-sided oxy-pyrrolidine-1- --Cw alkoxy, 2-oxo-piperidin-1-yl-C丨·3 alkoxy, morpholin-4-yl-CN3 alkoxy, 3-o-oxo-morpholine-4 -yl-C,.3 alkoxy, aminosulfonyl, Cw alkyl-aminosulfonyl, bis(CN3 alkyl)-amino thiol, pirolidin-1 -yl-can , pyridine-1 -yl-sulfonyl, oxime-4-yl-sulfonyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, fragrant C3·6 Cycloalkyl 'C3.6 cycloalkoxy, C3-6 cycloalkyl-Ci-3 alkyl, C3-6 cycloalkyl-Cw alkoxy, (hetero)aryl, (hetero)aryloxy, (hetero)aryl-Cw alkyl, (hetero)aryl-Cl.3 alkoxy, (hetero)aryloxy-CN3 alkyl, or tetrad-fol-3-yloxy, tetrahydrogen Anthracen-3-yloxy, tetrahydro Oxan _4_ yloxy, tetrahydrofuranyl-Cl-3 alkoxy or tetrahydropyranyl C!-3 alkoxy, wherein The above (hetero)aryl group is as defined above under R4. 135590.doc -64 - 200927115 More preferably 'R7 represents fluorine, gas, Cl-4 alkyl, hydroxy, Cw alkoxy, nitro, amine Base, Cl.3, deutero-amino 2-pyridyl-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl, 2-yloxy, 3-sided oxy-?琳-4-yl, -C!-3 alkylcarbonylamino, (hetero)aryl-carbonylamino, Cw alkyl-carboxylamino, N-(C!.3 alkyl)_Ci_3 Alkyl-amine, N-(C.sub.3 alkyl)-(hetero)arylcarbonylamino, NJCu alkyl VCw alkyl-sulfonylamino, NJC!.3 alkyl)-(hetero Arylsulfonylamino, decanoyl, (hydroxyimino)aminomethyl, (Cw alkoxyimino)aminoindenyl, carboxyl, Cw alkoxy-carbonyl, aminocarbonyl , CN3 alkyl-aminocarbonyl, bis(Cw alkyl)-aminocarbonyl, pyrrolidin-1-yl-number group, brigade. Dec-1-yl-rebel, morphin-4-yl-number, Ci_3 alkyl-carbonyl, carboxy-CN3 alkyl, Cw alkoxy-carbonyl-Cw alkyl, cyano C,.3 alkane , aminocarbonyl-Cw alkyl, Cw alkyl-aminocarbonyl-C丨.3 alkyl, bis(CN3 alkyl)-aminocarbonyl-Cw alkyl, pyrrolidin-yl-1-yl-carbonyl- Cw alkyl, piperidin-1-yl-carbonyl-Cw alkyl, morphin-4-yl.substyl-Cl.3 alkyl-cyano-Cw alkoxy, aminocarbonyl-Cw alkoxy, Cw alkyl-aminocarbonyl-Cw alkoxy, bis(Ci.3 alkyl)-aminocarbonyl-C!-3 alkoxy, pyrrolidin-1-yl-carbonyl-Cw alkyl-oxy, Piperidin-1-yl-carbonyl-Cw alkoxy, morpholin-4-yl-carbonyl-Chalkyl-oxy'-perylene-(^1.3 alkyl, 匸1-3 alkoxy_^11- 3 Hyun> base, ^11.4 基 base number-amino-Ci-3 appearance group, N-(Ci-3 hospital base VC). 4 alkyl group-amino group - 135590.doc -65- 200927115

Cw alkyl, 2-o-oxo-pyrrolidinyl)-yl-Cn3 alkyl, 2-tert-oxy-piperidin-1-yl-Cualkyl, 3-sided oxy-morpholine-4-yl- C..3 alkyl, hydroxy-Cw alkoxy, CN3 alkoxy-Cw alkoxy, aminosulfonyl, Cw alkyl-aminosulfonyl, bis(cN3 alkyl)-amine Styrene * trifluoromethyl, difluorodecyloxy, trifluoromethoxy, C3 · 6 ring hospital emulsion, tetrahydro beta drinking _3_ yloxy, tetrahydrogen. Nan-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-c丨_3 alkoxycarbonyl, tetrahydropyranyl-Cw alkoxy, (hetero)aryl or (hetero An aryloxy group, wherein the above (hetero)aryl group for R7 represents a phenyl group, a furyl group, a thienyl group, a thiol group, an 11 thiol group, an isoindole, a sylylene group, a mercapto group, an anthracene group吐基, 嗤二嗤基, 三吐基, 四哇基, >» than a bite base, a thiol group, a beta-pyridinyl group, a fluorenyl group or a triazinyl group, wherein any of these groups are optionally R10 Single or disubstituted. Most preferably, R7 represents fluorine, gas, Cw alkyl, hydroxy, Cw alkoxy group, amine group, Cw alkyl-carbonylamino group, Cw alkyl-sulfonylamino group, cyano group, (hydroxyimine) Aminomethyl, carboxy, C, .3 alkoxy-carbonyl, aminocarbonyl, C, .3 alkyl-aminocarbonyl, bis(Cw alkyl)-aminocarbonyl, hydroxy-Cw alkyl , Cw alkoxy-Cw alkyl, CN3 alkylcarbonyl-amino-Cw alkyl, hydroxy-Cw alkoxy, CN3 alkoxy-Cw alkoxy, trifluoromethyl, difluoromethoxy, a trifluoromethoxy group, a Cw alkylcarbonyl group, an aminosulfonyl group, a C 1.3 alkyl-amino group, a bis(C 1 -3 alkylol group) or a (hetero)aryl group, Is selected from the group consisting of phenyl, fluoren-1-yl, oxadiazolyl, pyridine 135590.doc • 66- 200927115 base, 1,2-dihydro-1-indolyl-2-sideoxy-< » 咬, 咬, 哒, and 2,3-dihydro-2-indolyl-3- oxo-pyridazinyl, each of which is optionally substituted by R10; especially 'R7 is fluoro, Gas, mercapto, hydroxy, decyloxy, amine, ethyl hydrazino, decylsulfonylamino, cyano, (hydroxyimino) amide thiol , ethoxycarbonyl, aminocarbonyl, decylamino-Wiki, dimethylamino-based, ethyl sulfhydryl, ethyl thiol, amine thiol, methyl amide , dimethylamino-based aryl, phenyl, <7-l- yl, 〇pyridinyl-3-yl, pyridine-4-yl, anthracene, 2,dihydro-1-indenyl-2-side Oxy-pyridin-5-yl, 1,2-dihydro-1-methyl-2-oxo-oxypyridyl-4-yl, pyrimidine-4-yl, 2-methyl-pyrimidin-4-yl, 2-methyl-pyrimidine _5-yl, 6-fluorenyl fluorenyl, 2,3-dihydro-2-indolyl-3-oxooxypyridazinyl or methyloxadiazolyl. R8 and R9, which are the same or different, represent fluorine, gas, bromine, Cl3 alkyl, trifluoromethyl, hydroxy, Cw alkoxy or cyanoguanidine. More preferably, R8&R9 independently represents fluorine, gas, methyl, and ethyl. a group, an isopropyl group, a trifluoromethyl group, a hydroxyl group, a decyloxy group, an ethoxy group or a lactyl group. Most preferably R8 represents a trans group or a methoxy group. If R and R are bonded to an adjacent carbon atom, then Together, it may additionally represent a methylenedioxy group, a difluoroindenylenedioxy group, an extended ethyldioxy group, a C35 alkylene group, or a benzene group together with the carbon atom to which it is attached, Oxazino, pyrazolo...methane, n-(Ci.3 alkyl) "thans salivation, N_(Ci3)", "mizu", triazolo, oxazole, thiazole, isoxazole And isothiazole ring, wherein any five member aromatic ring is additionally substituted by L and any six members are cyclically treated with one L· and/or one selected from fluorine, c丨_3 alkyl, three 135590.doc • 67· 200927115 Amino, Ci·3 alkylamino, bis(Cl·3 alkyl)amine, mono or disubstituted substituents via a radical or Ci-3 alkoxy.

Preferably, R8 and R9, when combined with an adjacent carbon atom, may additionally represent a methylenedioxy group, an ethylidene-1,2-dioxy group, a propyl group, a butyl group or a butyl group. The carbon atoms together form benzo, pyrazine, pyrazolo, imidazolium, N_(Cl_3 alkyl) pyrazolo, N-(C丨·3 alkyl)-imidazolium, triazolopyrene, oxazole And a thiazolo, isoxazole or isothiazolo ring, wherein any five member aromatic ring is additionally monosubstituted by L and any six members are optionally subjected to one L and/or one selected from the group consisting of fluorine, sulfhydryl and trifluoroethylene. The substituent of a methyl group, a methylamino group, a dimethylamino group, a hydroxyl group or a methoxy group is mono- or di-substituted. More preferably, R and R, if combined with an adjacent carbon atom, may additionally represent a methylenedioxy or ethylidene-2-dioxy group or, together with the carbon atom to which they are attached, form a benzo, pyrazine. And imidazolium, n_(Ci_3 alkyl)-imidazolium, triterpene, and thiazole ring, wherein benzo and pyrazine are cyclically substituted by - or two methyl groups and (d), N_Cd-based. Sit, oxazole and thiazole and ring-like conditions were additionally replaced by L. If the ground gas 2R9 is combined with an adjacent carbon atom, it can additionally indicate the first; 1 the broken atom connected to it - the shape - a certain * pyridine 4 - Λ, cyclopropyl 'four gas bite. 2. The base of the ethyl phenyl group is _4_ group, pyridine-3-A, 1 〇隹--, 222 Λ1·methyl methoxy- oxime, (d) or _methyl group · terminal 2 _ group substituted A ruthenium or a ring substituted with a methyl or dimethyl group, as appropriate. Instead, or oxazine 135590.doc •68- 200927115 L is preferably gas, Ci·4 alkyl, c3_6 cyclodextrin, slightly biting, 1_mercapto-pyridyl, 1-ethenyl - piperidinyl, tetrahydrofuranyl, trifluoromethyl, cyano, amine, ethylamino, methylsulfonic acid amine, carboxyl, C -3-alkyloxycarbonyl, aminocarbonyl, methyl Aminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, hydroxy, C|-3 alkoxy or phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, 12-dihydro-2 a pendant oxy-pyridyl group which is optionally substituted with one or two groups selected from the group consisting of fluorine, gas, C--3 alkyl, difluoromethyl, trifluoromethyl, cyano, Amidino, ethinylamino, methylsulfonylamino, carboxy 'Cw alkoxycarbonyl, aminocarbonyl, decylaminocarbonyl, dimethylamino-carbonyl, hydroxy, methoxy, Difluoromethoxy and trifluoromethoxy. More preferably, L is fluorine, decyl, ethyl, tert-butyl, (^^cycloalkyl, piperidinyl, 1-methyl-piperidinyl, ethionyl-piperidinyl, tetrahydrofuran Base, difluoromethyl, cyano, amine, ethyl, amino, methyl, thiol, anthracenyl, ethoxylated, amino group, methylamine Base Ik. group, monomethylamino group, amine aryl, trans, decyl or phenyl, pyridyl, pyridazinyl, pyridazinyl, pyrimidinyl, indole, 2_ Dihydro-2-oxo-pyridyl, optionally substituted with one or two groups independently selected from the group consisting of fluorine, methyl, trifluoromethyl, cyano, amine, ethenyl Amino group, methyl decylamino group, thiol, amino group, methylamino group, dimethylaminocarbonyl group, hydroxy group and decyloxy group. Optimum 'L is fluorine, methyl group, Cyclopropyl, i-ethinyl-piperidinyl, tetrahydrofuranyl, ethionylamino, methylsulfonylamino, carboxyl, thiol, methoxy or 135590.doc-69-200927115 0 bite Base, noisy base, π-mercapto group, 1,2-dihydro-2-sideoxy-° ratio bite base, The case is substituted by one or two thiol groups; in particular, L is a methyl group, a tert-butyl group, a cyclopropyl group, a tetrahydro alpha-flavored _2-based group, a thiophenanyl group, and a decyl group.比 咬 -3-yl, oxazin-3-yl, pirazin, 5-methylpyrazin-2-yl, 1,2-dihydro-2-oxoylpyridin-5-yl. R1Q Preferred means fluorine, gas, bromine, C -3-alkyl, difluoromethyl, trifluoromethyl, decyl, nitro, amine, ethylamino, methylsulfonylamino, rebellious a group, a Ci-4-alkoxy group, an amino group, a Ci_3 alkylamino group, a di-(C!-3 alkyl)-aminocarbonyl group, an aminosulfonyl group, a methylthio group, Mercaptosulfonyl, methylsulfonyl, phenyl, hydroxy, Cw alkoxy, difluoromethoxy or trifluoromethoxy. Most preferably, R1G represents fluorine, gas, methyl, difluoro. Methyl, trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy or trifluoromethoxy, most preferably R1G represents fluorenyl. R11 preferably denotes fluoro, Cu3 alkyl, phenyl, Hydroxy, C, _3 alkoxy, cyano, carboxy, Cm alkoxycarbonyl, aminocarbonyl, Cl 4 alkylamino, hydrazine carbonyl, bis(C|·4 alkyl)-amine More preferably, 'Rn denotes a fluorine, a Cw alkyl group, a hydroxyl group or a CK3 alkoxy group. Most preferably 'R11 represents a methyl group or an ethyl group. , propyl, hydroxy or methoxy, especially hydrogen, methyl or methoxy. R 2 preferably represents fluorine or Ci. 3 alkyl 'more preferred methyl or ethyl; and may be the same or different R 13 and R14 preferably denotes an ei-3-alkyl group. More preferably, R13 and R14 represent a methyl group. Certain terms used above and below to describe the compound of the invention 135590.doc-70·200927115 will now be defined in more detail. The term "substituted" as used herein means that any one or more of the hydrogens on the indicated atom are replaced by a group selected from the specified group, the restriction being such that the normal valence of the indicated atom is not exceeded, and the substitution is stable. Compound. The term halogen means an atom selected from the group consisting of F, CM, Br and I. The term Ch alkyl (wherein n may have a value of from 1 to 18) means 1 to 11 (: saturated, branched or unbranched hydrocarbon groups of the atom, examples of such groups include methyl, ethyl, n-propyl , isopropyl, butyl, isobutyl, tert-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. The term C2_n alkenyl (wherein η has a value of from 3 to 6) represents a branched or unbranched chain group having 2 to 2 c atoms and a C=C double bond. Examples of the group such as Yanhai include a vinyl group, a 1-propenyl group. , 2—propenyl, butenyl, 2·butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentyl, hexyl, 2 _Hexyl, 3_hexenyl, 4 hexyl, 5 _ ❹ ❹ C C2.n alkynyl (where n has a value of 3 to 6) means a branch having 2 to c atoms and CW Chain or non-branched bond hydrocarbon group.

Including ethynyl, propylpropanyl J propynyl, 2-propynyl, hydrazinobutynyl, 2-butyl, 3-butynyl, 1 oxime, phenyl, alkynyl, pentynyl, 3_pentynyl, 4·pentyne^, 2_hexynyl, 3·hexynyl, 4-hexynyl, 5-hexiyl, and the like. Unless otherwise 呤π, for the early morning I# D, the alkynyl group is connected to the C atom via position 1 and the remainder. So 'such as 1-propynyl, 2-propynyl, ! The terms "butynyl" and the like are equivalent to [five] 1 alkynyl, 1-, propyl 1 propynyl, 2-propynyl butyl 135590. doc • 71- 200927115 alkyn-1-yl and the like. It is also similarly applicable to c2-n alkenyl. The term C!_n alkoxy represents C^nalkyl-fluorenyl where the Ch alkyl group is as defined above. Examples of such groups include decyloxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, tert-butoxy, n-pentyloxy Base, isopentyloxy, neopentyloxy, third pentyloxy, n-hexyloxy, isohexyloxy and the like. The S-Ci.n^yl group represents a Ci-n-alkyl-C(=0) group, wherein the C--institution is as defined above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, t-butyl, tert-butyl A carbonyl group, a n-pentylcarbonyl group, an isopentyl group, a neopentylcarbonyl group, a third pentylcarbonyl group, a n-hexylcarbonyl group, an isohexylcarbonyl group or the like. The term (cycloalkyl) denotes a saturated mono-, di-, tri- or spirocarbocyclyl group having 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, bicyclol 2.6.] octyl, snail [4.5] fluorenyl, norpinyl, norbornyl, thiol, Donkey Kong Alkyl, etc. Preferably, the term "cycloalkyl" denotes a saturated monocyclic group. The term Ch cycloalkenyl denotes a (:5-"cycloalkyl group as defined above and additionally having at least one C=c double bond. (: "Cycloalkylcarbonyl represents (:3_"cycloalkyl.c(=fluorene) group, wherein the cycloalkyl group is as defined above. The term tris(Cm alkyl)decyl group contains the same or two or three Alkyl groups of different alkyl groups. 135590.doc -72- 200927115 The amine group of 术 匸 匸 匸 匸 匸 匸 含有 含有 含有 含有 含有 含有 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺Substituted, it is suitable for any form of group or residue. For example, if the alkyl group is monofluorinated or polyfluorinated as appropriate, it also contains a larger group (for example) An alkyl residue such as an alkoxy group, an alkylcarbonyl alkoxyalkyl group, or the like, or a (hetero)aryl group, if it is optionally substituted or substituted with a certain substituent or a group of substituents, Also included are larger groups (eg, (hetero)aryl-Cl·"alkyl, (hetero)aryloxy, (hetero)aryloxy-Cln-alkyl*, (hetero)aryl_C a (hetero)aryl group which is a part of an oxy group, etc. Therefore, if R4 or R7 has the meaning of, for example, a (hetero)aryloxy group, the (hetero)aryl residue is optionally monofluorinated or polyfluorinated. And the (hetero)aryl group particularly means a phenyl group, which also contains the meanings of monofluoro, difluoro, trifluoro, tetrafluoro and pentafluorophenoxy. The same applies to the CH2 group which can be passed through 〇, s, NR. a group or a residue substituted by c〇4S〇2. For example, a residue having a meaning of a hydroxy CM alkyl group in which a group may be substituted by c〇, which contains a carboxyl group, a carboxymethyl group, and a thiol group. The benzyl group, the thioethyl group, the fluorenylmethyl group methyl group and the benzyl group carbonyl group. The compound of the present invention can be obtained by a generally known synthesis method. Preferably, the compound is a compound. Obtained by the following method of the invention as described in more detail below. / 3 General strategy for obtaining a compound of the invention is described in the scheme; R2, R, X, m, n and oxime are as defined above and below. Meaning. The main reaction of assembling the double-ring framework is the intramolecular combination of the amine functional group and the scavenging group, which leads to the formation of a stilbene bond. (4) The functional group and the functional fusion can be at a high temperature of 135590.doc •73- 200927115 (preferably 20 with Between 200 ° C), in the presence or absence of additives. Add additives such as molecular sieves or orthoesters formed during the reaction or other additives (such as alkalis such as hexamethyldiazide azide) ) or broad acid can promote the reaction. However, a more preferred reaction is to use a more reactive carboxyl functional entity (such as a mercapto halide, vinegar, thioester, sour liver, mixed acid or ethylene) in another reaction prior to the reaction step or in situ. steel). Preferred broths are sulfhydryl chlorides and fluorenyl fluorides. Preferably, the sulfuric acid is derived from, for example, methanol/methyl mercaptan, ethanol/ethyl sulfur® alcohol, 2,2,2-trifluoroethanol, phenol/thiophenol, substituted phenol/thiophenol (such as 4_nitro- or pentafluorophenol), hydroxyheteroaryl (such as hydroxybenzotriazole, transamination of di-salt or hydroxytriazine) or N-hydroxypodoximine. Preferred mixed anhydrides are derived from alkyl carboxylic acids (e.g., pivalic acid), carbonates (e.g., ethyl sulphate and ethyl carbonate), urethanes (e.g., N, N-dimethyl urethane) , squaric acid (such as dimethyl phosphate or (Me2N) 2p (〇) 〇 H) or urea (such as dicyclohexyl pulse, dimethyl urea or tetramethyl urea). In addition, it is also possible to use an N-derivative derivative derived from an argon hetero group such as imipenem, triterpenoid, tetraterpene or „bite (such as -methylaminopyridine) for activating the carboxylic acid function. Some of the more common reagents are N,N'-carbonyldiimidazole, dicyclohexylcarbodiimide, (benzotriazolyloxy)dipiperidinylcarbamate hexafluorophosphate or tetrafluoroborate, Stupid triazole _丨_yloxy)dipyrrolidinyl carbon rust hexafluorophosphate or tetrastearate, 1·(3-dimethylaminopropyl)_3_ethylcarbodiimide Filler, P〇Cl3, SOCl2, (c〇cl)2, c〇ci2, aryl ruthenic acid, TiCl4, (Me0)2P0C1, cyanuric chloride, hydroxy benzotriazole, 1-hydroxy-7 -azabenzotriazole, benzotriazole-oxime-oxyl (dimethyl 135590.doc -74· 200927115 amide) hexafluorophosphoric acid or tetrafluoroboric acid, benzotriazole-bu-oxygen Base three. Bilo bite squamous six-gas phosphate or tetrafluorofolate, (7. aza. benzotrisinyloxy) tripyrrolidinyl hexafluorophosphate or tetrafluoroborate, hydrazine _(benzotriazol-1-yl)-N,N,N,,N,-four Methyl hydrazine hexafluorophosphate or tetrafluoroborate, bismuth-(7-aza-m-benzotrizan 3'3_tetramethyl hexa-phosphate or tetrafluoroborate. This reagent series only indicates A small number of possible reagents for activating carboxylic acid functional groups. A wide variety of other reagents are known and can be used. Reactive carboxylic acid derivatives can also be used as intermediates for oxime reagents which are also sufficiently reactive for this conversion. The activation step and the subsequent indoleamine formation step are generally preferably carried out with additional additives such as a base such as ethyldiisopropylamine, triethylamine, alkali metal carbonate, pyridine, 4-dimethylaminopyridine, imidazole, The reaction is carried out in the presence of methylaluminum amination, lithium alkoxide 'alkali metal cyanide or alkali metal hexamethyl azide. The reaction is preferably carried out in an organic solvent, but it can also be carried out in an aqueous solvent. The solvent is dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofurfuran, hexane, ether, dioxane, dimethoxyethane, Dioxane, diethylene, toluene, #, acetic acid, brewing, 喧# bite or mixture thereof The reaction can be carried out at -8 (TC to 22 Torr, preferably -1 Torr. (: with 120 ° C. Subsequently, the indole amine group is reduced to give a second amine. This is converted to a well-known reaction, which can for example Using L1AIH4, hydrogen in the presence of a catalyst, for example, NaBH4 in the presence of iodine, LiBH4, borane, sodium in propanol, cijiH, decane in the presence of a transition metal such as ruthenium (eg EhSiH), 9_bbn,

LiBH3NMe2 or Et3SiH is combined with LiEt3BH. It can be used at _78 ° C to 2 ° ° C, preferably between -1 (TC and uoi, such as tetrahydrofuran, 135590.doc • 75- 200927115 ether, dimethoxyethane, dioxane, a solvent for alkanes, benzene, toluene, dioxins, alcohols, water or mixtures thereof, but only a few of these solvents can be combined with certain reducing agents. This strategy is highly suitable for the synthesis of structural compounds 1.1 to 1,10 .

Process 1 establishes a double loop skeleton strategy 1

Y = See herein Another common synthetic route to obtain a compound of the invention is outlined in Scheme 2; R2, R3, X, m, n and oxime have the meanings as defined above and below. The bicyclic framework is formed by intramolecular reductive amination of a first amine with a ketone functional group. Reductive amination is important in organic chemistry and can, for example, use hydrogen in the presence of a transition metal catalyst such as a catalyst derived from Ni, Rh, Pd or Pt, a butterfly hydride reagent (eg, a hydrogen hydride, an aryl group) Sodium hydride or triethyl methoxy group; sodium hydride), combined with hydrochloric acid,

PhSiHs and Bi^SnCh, hydrazine, οΗμ or formic acid or a salt thereof. Some of these agents are preferably used in combination with an addition such as an acid such as acetic acid or a mineral acid. The reaction is preferably carried out in an organic solvent or an aqueous mixture (for example, methineamine, dimethylacetamide, oxime-methylpyrrolidone, ruthenium ketone, tetrahydrofuran, hexane, ether, dioxins). The reaction may be carried out at -80 ° C to 200 ° C, preferably -10 °, in calcination, dimethoxyethane, _ & alkane, di-ethane, toluene, benzene, alcohol, water or a mixture thereof. Between C and loot 135590.doc • 76- 200927115 Process 2 Strategy for establishing a double-ring skeleton 2 R.

|[ γ intramolecular reductive amination

A R3 R3^^^^ΛSc^)° For example NaHB(OAc)

Or the strategy shown in NaBH3CN, NH2 Scheme 3 (wherein R2, R3, X, m, η and ο have the meanings as defined above and below) is based on the reductive amination reaction already described in Scheme 2 An effective method. The reaction conditions described therein can be similarly employed herein. Process 3 strategy for establishing a double loop skeleton 3

II I intramolecular reductive amination r3/\xx^)〇 For example NaHB(OAc)3

Nn or NaBH3CN

Scheme 4 (wherein R2, R3, X, m, η and 〇 have the meanings as defined above and below) demonstrates another method of assembling a bicyclic framework. This method is the intramolecular alkylation of a suitable electrophile with a nitrogen group and a side chain. The nitrogen group may be an amine group, that is, Ra represents, for example, hydrogen, a methyl group, a propyl group, a benzyl group or a dimethoxy group, or an amine group, that is, Ra represents, for example, a methoxy group. , oxy-oxyl, propyloxyoxy, tert-butoxy, trifluoromethylcarbonyl, ethyl hydrazino, 2,2,2-trisethoxycarbonyl, tolylsulfonate Sulfhydryl, phenyl styrene, methoxyphenyl fluorenyl, nitrophenyl fluorenyl, 2,2,2-trisylethylsulfonyl or 2-trimethyldecylethyl醯基. The nitrogen functional group and the electrophilic CSf>3 center in the side chain (ie, LG in Scheme 4 represents, for example, gas, bromine, argon, hydrazine, acetophenoxy or trifluoro 135590. Doc -77- 200927115 Methylsulfonyloxy) in a base (such as triethylamine, ethyldiisopropylamine, diazabicyclodeven, metal carbonate, metal tert-butoxide, metal test) The reaction is carried out in the presence of diisopropylamine, butyl lithium or sodium hydride. Preferably, the strong base is between -70 and 10 ° C, preferably between _3 〇 and 6 〇〇 c at, for example, N-decyl pyrrolidine _, dimethyl sulfoxide , tetrahydrofuran, hexane, hydrazine

Ether, dioxane, dimethoxyethane, toluene, benzene, tert-butanol, isopropanol or a mixture thereof is used in combination with the amine. The weak bases listed are preferably between hydrazine and 140 ° C, preferably between 20 and 12 Torr, at a temperature of two gas, dimethylformamide, N-methyl oxime (four) , dimethyl sub-sector, tetra-negative, hexane, ether, dioxane, dimethoxyethane, toluene, benzene, methanol, ethanol, second butanol, isopropyl acid, water or a mixture thereof A combination of amines is used. For the indoleamine, the article originally reported by Mhsun〇bu can also be used. Therefore, the side chain detachment-based LCHS is used with azobis-acidic acid (for example, diethyl azodicarboxylate, diisopropyl azodicarboxylate or azodicarboxylic acid), and The gamma phosphine (e.g., diphenylphosphine or tributyl scale) is produced in situ from the base. Suitable solvents may be selected from the group consisting of dimethyl ketoamine, n-methyl acetonate, gas methyl hydrazine, tetrahydrofuran, morphologies, ethers, dioxins, dimethoxy methoxy, and mixtures thereof. The reaction is preferably carried out between 〇 and 1 〇〇 °C. The opposite approach (ie LG means NHRa indicates LG) is also applicable. The reaction conditions are the same as the initial route. Process 4 strategy for establishing a double-ring skeleton 4 135590.doc •78· 200927115

Other generally applicable methods are based on electrophilic aromatic substitution reactions (Scheme 5); R2, R3, m, η and oxime have the meanings as defined above and below. Thereby, the aromatic moiety of the molecule reacts with the activated carbon atom of the nitrogen heterocycle to form a bicyclic framework. The reactive intermediate has a (partially) positively charged carbon atom in the nitrogen heterocycle which can be formed by the addition of citric acid to the olefinic bond or by activation of a suitably positioned leaving group. A large number of Bronstedt acids and Lewis acids have been described for use in this conventional reaction, which can also be used herein. The following list is intended to provide some of the more widely used substances: hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid, scaly acid, P4〇10, tri-acetic acid, acinic acid, toluic acid, difluoroanthracene acid , Sc(OTf)3, SnCl4, FeCl3, AlBr3, A1C13, SbCl5, BC13, BF3, ZnCl2, montmorillonite, p〇Cl3& PCI5 depending on the tendency of the radical to be substituted and the electronic properties of the aromatic, 0 It is necessary to use an acidic catalyst which is more or less effective. In addition to the acidic catalyst, a silver salt (e.g., AgOTf) can be used in the reaction using a complex as a leaving group. Preferred solvents are hydrocarbons (such as hexane or cyclohexane), gasified hydrocarbons (such as gas or triethylene bromide), perfluorinated hydrocarbons, benzene, gasified benzene, heteroaromatics (such as quinine). Porphyrin), dimethoxyethane, dioxane, ether, ionic liquid or mixtures thereof. The reaction can be carried out between 丨〇〇c and 220〇c, preferably between 20 c and 1 80 C. The reaction can also be carried out under microwave irradiation. This synthetic strategy is particularly applicable to structural compounds having multiple electron aromatics 135590.doc -79- 200927115 1.1 and 1.3 to 1.10. Process 5 Strategies for Establishing a Double Loop Skeleton 5

^PG

LG = for example oh, 〇S02Me, OS02Tol, 0S02CF3, Cl, Br, I, 3-队3-坑勒 〇c〇<ClJr^*),... ’ PG = protecting group, eg Me or Bn, or CORi

The bicyclic structural compound can also be obtained via the route described in Scheme 6; m has the meaning as defined above and below, and PG and PG are protecting groups such as trialkyldecylalkyl for PG, and for pG , in terms of the base or base. The cyclization system is realized by adding a radical intermediate generated by a tri-sulfonium group and a chl〇rine abstracting reagent to a double bond. The suitable gas extraction reagent is a radical initiator (such as an even Nitrogen bisisobutyronitrile or dibenzyl hydrazide peroxide) is formed by BujnH and (MhSihSiH, BwSn. and (MhSihSi.). The reaction is preferably at high temperature in benzene, toluene, cyclohexyl or hexane. This method is specifically reported to refine the compound to a desired compound. The compound can be reduced to an amine and the right-end protecting group can be removed and the CH2C in the left part of the molecule is 135 135590.doc 200927115 This is accomplished by conversion to an aromatic species as described above. These transformations are described above and below, and transformations of similar compounds are known from the organic chemistry literature (see, for example, Thomas L: Gilchrist, VCH, Weinheim, 1995). Strategy 6 establishes a double loop skeleton strategy 6

In addition to the described strategy, a number of additional methods of constructing the bicyclic system of the invention can be devised and reported in the literature (see, for example, Met/. C/2ew. 1970, 13, 630-634; Chem. Rev. 1977, 77). , 1-36; «/. Med. Chem. 1979, 22, 537-553; J. Org. Chem. 1984, 49, 4033-4044; J. Med. Chem. 1996, 39, 1956-1966; Heterocycles 1996 , 43, 15-22; J. Med. Chem. 2002, 45, 3755-3764; J. Org. Chem. 2006, 77, 2046-2055; and references cited therein). Thus, the above strategy is in no way intended to limit the possible synthetic pathways for obtaining the compounds of the invention, and is intended to show only a few ways by way of example. The synthetic route may depend on the use of a protecting group. Suitable protecting groups for individual functional groups and their removal are described above and can be similarly employed (see also Grow/75, Philip J. Kocienski, 3rd edition, Georg

Thieme Verlag, Stuttgart, 2004 and references cited therein). The compounds of the invention may also be advantageously obtained using the methods described in the following examples, for which purpose such methods may also be combined with methods known to those skilled in the art from the literature. 135590.doc -81 - 200927115 As already mentioned, the compounds of the formula i of the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular inhibition of the enzyme 11β-hydroxysteroid dehydrogenase (HSD) 1 . The biological properties of the new compounds can be studied as follows: Test compounds for 11 β-HSD 1 in vitro inhibition using HTRF (homogeneous time difference fluorescence) technique (cisbio international, France) to detect corticosterone in human liver microsomes ( Cortisterone) Cortisol produced to determine. Briefly, compounds were incubated for 1 hour at 37 °C in Tris buffer (20 mM tris, 5 mM EDTA, pH 6.0) containing NADPH (200 μΜ) © and corticosterone (80 ηΜ). The cortisol produced in the reaction is then detected by a competitive immunoassay involving two HTRF conjugates: cortisol linked to XL665 and anti-cortisol antibody labeled with a cryptate compound. The incubation period for the detection reaction is usually 2 hours. The amount of cortisol was determined by reading the time-lapse fluorescence of the wells (Ex 320/75 nm; Em 615/8.511111 and 665/7.5 11111). Then calculate the ratio of the two transmitted signals (Em665*10000/Em615). Each assay consisted of a vehicle control replacement product culture as an uninhibited control for cortisol production (100% CTL; "high value") and incubation with carbenoxolone as a fully inhibited enzyme and cortisol background Control (0% CTL low value). Each assay also included a cortisol calibration curve to convert the fluorescence data to cortisol concentration. The percent inhibition of each compound was determined relative to the carbenoxin signal and produced a lC5〇 curve. The inventive compounds of formula I may, for example, have an IC50 value of less than 10000 nM, especially less than 1000 nM, optimally less than 100 nM. In Table 2, the compounds of the invention (designated in Table 3) are summarized and as above The inhibitory activity thereof is determined. 135590.doc -82- 200927115

Table 2 Example Ιΐβ-HSD Example Ιΐβ-HSD Example Ιΐβ-HSD Example Ιΐβ-HSD No. IC5〇(nM) No. IC5〇(nM) No. IC5〇(nM) No. IC5〇(nM) 1 285 80 40 168 561 249 265 2 741 81 463 169 950 250 53 3 85 82 56 170 626 251 66 4 56 84 139 171 1651 252 61 5 3099 85 89 172 1724 253 78 6 1058 86 2399 173 1694 254 742 7 262 87 622 174 406 255 742 8 3356 88 171 175 344 256 222 9 1979 89 62 176 603 257 209 10 1775 90 468 177 8906 258 33 11 530 91 711 178 159 259 115 12 792 92 1106 179 199 260 181 13 1609 93 2058 180 1318 261 47 14 734 94 6723 181 147 262 73 15 354 95 3842 183 155 263 71 16 360 96 95 184 1147 264 78 17 1378 97 1134 185 5375 265 22 18 3685 98 125 187 1957 266 42 19 658 99 285 188 2916 267 66 20 254 100 564 189 2273 268 931 21 669 102 1459 190 1651 269 63 22 5042 103 86 191 571 270 99 24 134 104 1388 192 434 271 50 25 686 105 1332 193 360 272 44 26 2889 106 2961 194 642 273 35 27 629 107 2546 195 2479 274 51 28 3684 108 140 196 781 275 25 29 172 7 109 1457 197 3830 276 34 30 1398 111 1604 198 435 277 34 31 88 112 1234 199 137 278 438 32 915 113 3633 200 117 279 52 33 3493 115 1587 201 53 280 1264 34 3883 116 3854 202 66 281 918 35 672 117 1423 203 125 282 409 36 3665 118 72 204 27 283 55 37 998 119 1548 205 38 284 666 38 1444 120 3843 206 47 285 150 39 1590 121 4122 207 224 286 47 40 542 122 818 208 238 287 61 41 589 123 297 209 40 288 901 42 4527 124 658 210 68 289 121 43 1757 125 989 211 31 290 72 44 200 126 1270 212 1945 291 183 135590.doc -83- 200927115 Example Ιΐβ-HSD Example Ιΐβ-HSD Example Ιΐβ-HSD Example Ιΐβ-HSD No. IC5〇(nM) No. IC5〇(nM) No. IC5〇(nM) No. IC5〇(nM) 45 384 127 1466 213 2972 292 502 46 97 128 1291 214 5711 293 27 48 364 129 5848 215 1730 294 146 49 168 130 1608 216 1715 295 35 50 3002 131 361 217 410 296 32 51 629 132 958 218 2708 297 895 52 101 133 941 219 160 298 99 53 321 134 1228 220 549 299 352 54 529 135 3520 221 2433 300 115 55 746 137 3621 222 1 24 301 32 56 725 138 2805 223 106 302 35 57 137 139 92 224 21 303 717 58 62 140 48 225 98 304 251 59 36 141 59 226 1410 305 153 60 228 142 689 227 25 306 978 61 798 143 123 228 236 307 979 62 109 144 2561 229 68 308 210 63 216 145 108 231 146 309 184 64 753 146 384 232 132 310 214 65 29 147 1013 233 144 311 424 66 822 148 556 234 3119 312 103 67 32 149 374 235 95 313 61 68 372 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 335 242 547 320 165 75 395 160 2175 243 113 321 1167 76 166 161 1750 245 257 323 620 77 144 162 1091 246 637 324 121 78 67 163 249 247 190 325 771 79 1367 167 291 248 1514 330 44

In view of the ability to inhibit the enzyme 11β hydroxysteroid dehydrogenase (HSD) 1, the compounds of the formula I according to the invention and their corresponding pharmaceutically acceptable salts are theoretically suitable for therapeutic and/or prophylactic treatment which can be deprived of 11β-hydroxysteroids. All conditions or diseases affecting the inhibition of hydrogenase (HSD) 1 activity. Thus, the compounds of the invention are particularly useful for the prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes, diabetic complications (such as retinal 135590.doc-84-200927115 disease, kidney disease or neuropathy, Diabetic foot disease, ulcer, macrovascular disease, traumatic injury: slow or bad), metabolic acidosis or rickets, reactive hypoglycemia, sputum aureus, glucose metabolism, 姨, resistance, low Xie syndrome has different sources of dyslipidemia, atherosclerosis and related diseases, obesity, high blood stasis, chronic stress, edema and hyperuricemia. These substances are also suitable for preventing the degeneration of beta cells, such as pancreatic cells or necrosis. These substances are also suitable for improving or restoring the function of the knee cells and also increasing the number and size of pancreatic beta cells. The compound of the present invention can also be used as a diuretic or anti-hypertensive agent and is suitable for the prevention and treatment of acute renal failure. Furthermore, inhibition of hydroxysteroid dehydrogenase (HSD) 1 has been shown to reduce intraocular pressure in individuals with high intraocular pressure, and thus compounds can be used to treat glaucoma. <The compound may be beneficial in view of the effect of ΐβ-hydroxysteroid dehydrogenase (HSD) i on the cortisol content of the interaction with the glucocorticoid $ body and the known effects of excess glucocorticoids in the loss of the genital machine Anti-osteoporosis effect. Stress and/or glucocorticoids have been shown to affect cognitive function, and excess cortisol is associated with loss or dysfunction of the brain's nerves. Treatment with a steroid-based steroid dehydrolactinase (HSD) 1 inhibitor can cause improvement or prevention of cognitive impairment. These compounds are also suitable for the treatment of anxiety or depression. The dynamic interaction between the immune system and the HPA (hypothalamic pituitary-adrenal) axis is known, and glucocorticoids contribute to the balance between cell-mediated responses and humoral responses. In certain disease conditions, such as tuberculosis, leprosy, and psoriasis, the immune response usually favors a humoral response. Cell-based responses will be more appropriate. The Ιΐβ-hydroxysteroid dehydrogenase (HSD) i inhibitor will add a 135590.doc •85- 200927115 strong immune-associated transient immune response to ensure a cell-based response and thus be suitable for immunomodulation. DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention (including physiologically acceptable salts thereof) are useful for the prevention or treatment of diabetes, especially diarrhea and type 2 diabetes and/or diabetic complications.剂量 剂量 The dose required to achieve the corresponding activity for treatment or prevention will generally be determined by the patient's physician depending on the nature and severity of the administration of the compound, the patient, the disease or condition, and the method of administration and frequency of administration. Conveniently, the dosage by intravenous route may be from 1 to 100 mg, preferably up to "mg" and by the oral route, from 1 to 1000 mg, preferably from 1 to 100 mg, in each case 1 to 1 per day 4 times. To achieve this (4), the compound prepared according to the invention may be combined with other active substances, together with other active substances, and, for example, together with corn powder, Lactose, (iv) sugar, microcrystalline cellulose, stearic acid, polyethylene base, glyceric acid, tartaric acid, water, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, Propylene glycol, hexadecyl octadecyl alcohol, methine cellulose or a fatty material such as stearin, or a suitable mixture thereof, formulated to produce a conventional galemc preparation, such as a plain or coated lozenge Capsules, powders, suspensions or suppositories. The compounds of the invention may also be used in combination with other active substances, especially for the treatment and/or prevention of the above mentioned diseases and conditions. The active substances suitable for such combinations include, for example, Strengthening this hair', a tribute to the steroids Dehydrogenase = D) 1 inhibitor for the therapeutic effect of one of the indications and / or

a substance such as 135590.doc-86-200927115, which has a reduced dose of steroidal dehydrogenase (Η ς m , P wind enzyme (hsd) I inhibitor. The therapeutic agent suitable for the combination includes, for example, an antibiotic Diabetic agents (such as metformin), sulfonyl urea (such as glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide (repaglinide), thiophene. Sodium diketone (eg rosiglitazone, pioglitazone), SGLT 2 inhibitor (eg dapagliflozin, sergliflozin) )), PPAR-γ agonists (eg GI 262570) and antagonists, PPAR-γ/α modulators (eg KRP 〇 297), α-glucosidase inhibitors (eg acarbose, Voglibose, DPPIV inhibitors (eg, statin; sitagliptin, vildagliptin, esarepril; j (Saxagliptin), alogliptin, Alogliptin, BI 1356), α2-antagonists, insulin and insulin analogs, GLP-1 and GLP-1 analogs (eg Amytin-4 or amylin. The list also includes protein tyrosine phosphatase 1 inhibitors; substances that affect uncontrolled glucose production in the liver (such as glucose-6-phosphate) Enzyme or fructose-1,6-diphosphatase, ® inhibitor of glycogen phosphorylase, glycoside receptor antagonist and phosphoenolpyruvate carboxykinase 'hepatose synthase kinase or pyruvate dehydrogenase Inhibitors and glucokinase activators); lipid lowering agents (such as HMG-CoA reductase inhibitors (such as simvastatin, atorvastat, atorvastatin), fiber esters (nbrate) (eg bezafibrate, fen〇nbrate, niacin and its derivatives); PPARa agonist; ppAR-delta agonist; ACAT inhibitor (eg Avamai) Avasimibe or cholesterol absorption inhibitors (such as ezetimibe 135590.doc • 87 - 200927115 (ezetimibe)); bile acid-binding substances (such as cholestyramine); ileal bile acid transport inhibitors; elevated HDL a compound (such as a CETP inhibitor) or an ABC1 modulator, or used to treat obesity Sexual substances (such as sibutramine or tetrahydrolipostatin, SDRI, axokine, leptin, leptin mimic, cannabinoid 1 receptor antagonist, MCH-1 receptor antagonist, MC4 receptor agonist, MC4 receptor agonist, NPY5 or NPY2 antagonist or β3 agonist (such as SB-418790 or AD-9677) and 5HT2c receptor agonist) . In addition, with drugs that affect high blood pressure, chronic heart failure or atherosclerosis (such as A_II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists, central anti-high resistance) An example of an angiotensin II receptor antagonist is a combination of a blood pressure agent, an alpha 2 adrenergic receptor antagonist, a neutral endopeptidase inhibitor, a platelet aggregation inhibitor, and other substances or combinations thereof. Candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan Irbesartan), EXP-3 174, L-158809, EXP-3312, olmesartan medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423 , BR-9701, etc. Angiotensin II receptor antagonists are preferably used in combination with diuretics such as hydrochlorothiazide for the treatment or prevention of hypertension and diabetes complications. It is suitable for the treatment or prevention of gout in combination with a uric acid synthesis inhibitor or a uric acid. 135590.doc -88 - 200927115 with GABA-receptor antagonists, Na channel blockers, topiramat, protein kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors The combination can be used to treat or prevent diabetic complications. The dose of the above combination is usually 1/5 of the recommended minimum dose to 1/1 of the recommended dose of positive f. Thus, in another aspect, the invention relates to the use of a compound of the invention or a physiologically acceptable salt of the compound in combination with at least one of the above active substances as a combination conjugate for the preparation or treatment of an enzyme 1 1 Use of a pharmaceutical composition for a disease or condition affected by inhibition of a steroid dehydrogenase (HSD) 1. It is preferably a metabolic disease, especially one of the above diseases or conditions, more particularly diabetes or diabetic complications. The use of a compound of the invention or a physiologically acceptable salt thereof in combination with another active substance can be carried out simultaneously or at staggered times, but especially at short intervals. If the system is administered at the same time, the two active substances are administered to the patient together; and if the system is used at the staggered time, the two active substances are less than ® or equal to 12 hours (but especially less than or equal to ό hours). The patient is given during the time period. Accordingly, in another aspect, the invention relates to a compound comprising a compound of the invention or a physiologically acceptable salt of the compound and at least one of the above-mentioned active substances as a combination partner, optionally with one or more inert carriers and/or A pharmaceutical composition of a diluent. Thus, for example, the pharmaceutical compositions of the invention contain the formula of the invention! The compound or a physiologically acceptable salt of the compound is in combination with at least one vascular stress 135590.doc •89·200927115 π receptor antagonist, optionally in combination with one or more inert agents and/or diluents. The compound of the present invention or a physiologically acceptable salt thereof and the additional active substance to be combined therewith may be present together in one formulation (for example, a tablet or capsule) or separately in two identical or different formulations (for example, so-called In the form of a component kit). The following examples are intended to illustrate and not to limit the invention: Preparation of starting compounds:

© Example I

Phenylacetylene (15·4 mL) was added to 2·^ _4_ decyl-pyridine (20.0 g), Cul (2.2 g) and Pd(PPh3)2Cl2 (4.1 g) in triethylamine maintained under argon atmosphere. In a mixture of (600 mL). The mixture was searched overnight at ambient temperature. Next, water was added and the resulting mixture was extracted with diethyl ether. The combined organic extracts were washed with brine and dried (MgSCU). The solvent was removed under reduced pressure and the residue was purified (jjjjjjjjjj Yield: 18.6 g (83% of theory). Mass spectrum (ESI+): m/z = 194 [M+H] + Example 135 135590.doc -90- 200927115

The 4-methyl-2-phenylethynyl-ruthenium ratio was mixed under a hydrogen atmosphere (50 psi) at ambient temperature. A mixture of (18.2 g) and 1 〇 % / carbon (2.0 g) in methanol (3 〇〇 mL) was added until the bond was completely reduced (2 〇 h). The mixture was filtered and the solvent was removed under reduced pressure.

A W yield: 17.6 g (95% of theory) Mass spectrum (ESI+): m/z=198 [M+H]+

Example III

Block I,4-Dimethyl-2·phenethyl-pyrrolidine Add iododecane (8.3 mL) to 4-methyl-2-phenylethyl-pyridine (17.5 g) in acetonitrile (70 mL) In the solution. The resulting solution was stirred overnight at room temperature. Then another portion of iodonane (28 mL) was added and the solution was further agitated for 14 h at about 35 °C. After cooling to room temperature, the precipitate was separated by filtration, washed with acetonitrile and at 5 Torr. (: under dry. Yield: 20_9 g (69 理论 / 理论 of theory) Mass Spectrum (ESI+): m/z = 212 π, 4_ dimethyl 2 _ phenyl ethyl 〇 〇 ] **

Example IV 135590.doc -91 · 200927115

1,4-Dimethyl-6-phenethyl 4,2,3,6-tetra-argon-pyridine and L4-dimethyl-2-phenylethyl-I,2,3,6-four gas bite Sodium borohydride (2.9 g) was added in portions to 1,4-dimercapto-2-phenylethyl 峨 ° (20.9 g) and sodium hydroxide (23.9 g) in water (60 mL) and methanol In a mixture of (75 ❹ mL). The mixture was at 60. (: stirring for 1 h and then cooling to room temperature. The reaction mixture was extracted with diethyl ether and the organic extract was dried (MgS04). After removal of the solvent, 'by gas chromatography (di-methane/decyl alcohol 30:1-9: 1) Purification of the residue gave a mixture of the title product (~3:). Yield: 16.4 g (61% of theory) Mass (ESI+): m/z=216 [M+H] +

Example V

1,11-Dimethyl-11-aza-tricyclic [8.3.1.0*2,7*] 1,4- 2,4,6-triene dissolved in polyphosphoric acid (5 mL) at 150 ° C 1,4-Didecyl-6-phenethyl-1,2,3,6-tetrahydro-pyridine and 1,4-dimercapto-2-phenylethyl-1,2,3,6 a mixture of tetrahydro-pyridine (about 3:1, 1.0 g) for 2 d. After cooling to about 80 ° C, water (30 mL) was added and the mixture was vigorously stirred for 5 min. Next, the mixture was cooled in an ice bath, more water was added, and the mixture was alkalized using a 40% aqueous NaOH solution. The resulting mixture was extracted with ethyl acetate, and the combined extracts of 135590.doc: 92-200927115 were washed with brine and dried (MgS 4). The solvent was removed under reduced pressure to give the title product. Yield: 0.76 g (76% of theory). Mass. (ESI+): m/z = 216 [M+H] + The following compounds are obtained in the same manner as in Example V: (1) 1_methyl-10-aza- Ring [7.2.1.0*2,7*]12-2,4,6-triene

Mass Spectrum (ESI+): m/z = 174 [M+H] + <RTIgt;</RTI>> 2-benzyl-4-mercapto-2,5-dihydro-pyrrolecarboxylic acid tert-butyl ester was used as starting material.

Instance VI

1-methyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradec-2,4,6-triene was added dropwise to 1-chloroethyl vinegar (3.8 mL). 1,11-Dimercapto-11-aza-tricyclo[8.3.1 ·〇*2,7*]tetradecyl-2,4,6-triene (0.75 g) and NaHC03 (2.9) cooled in an ice bath g) in a mixture of 1,2-dioxaethane (3,5 mL). The reaction mixture was allowed to warm to room temperature in a cooled bath and stirred overnight. The reactor was added with chloranil (20 mL) and the slab was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was evaporated mjjjjjjj The resulting solution was mixed at reflux temperature for 2 h. The solution was concentrated and the residue was purified EtOAcjjjjjjj 135590.doc •93- 200927115 Yield: 0.11 g (theoretical 160/〇) The following compounds are similar to Example VI to obtain the indole-6-alcohol (1) diindenyl group...-tetrahydro-he is -曱 bridge-stupid And (4) nitrogen

The starting material was obtained from 3,11,11-trimethyl-2,3,4,5-tetrahydro-111_2,6-methyl bridge_stupyl-piperidinium. © [d]azepine-6·alcohol is similar to EP 28717 (1981) from 2-benzyl-1,3,3-tricarboxylic acid methyl ester (2) 8-hydroxy·2,3,4,5-four Hydrogen-1Η-2,6-methyl bridge-benzo[d]azepine_6_A

Starting material 8-yl-3-methyl-2,3,4,5-tetrahydro-1Η-2,6-methyl bridge_stupid and φ[d]azepine-6-decanoate methyl ester can be similar乂MeA C/^w. 1962, 5,357 361 and US 3687957 (1972) from 8-methoxy-3-methyl_1_sideoxy-2,3,4,5-tetrahydro-iH -2,6-anthracene-benzo[d]azepine-6-carbonitrile. The methoxy group on the aromatic ring can be cleaved by using boron tribromide in dioxane or hydrobromic acid in acetic acid (see, for example, 1/. from .67^. 1992, 35, 4135-4142). J. Mec/· CTzew. 2004, 岑 7, 165-174). The starting material can also be obtained according to the procedure J by reacting a compound example χχιι (丨) with boron tribromide. 135590.doc •94- 200927115

Phenyl-1,2,3,4,5,6-hexahydro-2 6-methyl bridge·stupid (3) 11,11-dimethyl [d]azepine-8-ol

Starting material 3, U, U_trimethyl_6_phenyl-10-^6 gas^methyl bridge-benzo[d]azane_8-alcohol can be obtained as described in DE 2027〇77 (197〇) : 〇(4)6·propyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-stupidated as nitrogen^8•ol

The starting material 3-methyl-6-propyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge_stupid[d]azepine-8-ol can be as X Md C/z is 1963, obtained as described in <5,322-5. (5) 6-Methyl-1,2,3,4,5,6-hexahydro-2,6-indole bridge-benzo[d]azepine_8-ol

The starting material 36_dimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzone--8-ol can be obtained as described in 丄I960, 25.

Example VII 135590.doc -95· 200927115

(Methoxy-3-lateral oxy-di-negative succinyl) methyl acetate methyl acetate concentrated sulfuric acid (3.0 mL) was added to 5-oxonium oxide 1-hydroquinone __3 dissolved in methanol (100 mL) - acetic acid (13 〇§). The solution was stirred at reflux temperature for 4 h and then cooled to room temperature. About two-thirds of the methanol was removed under reduced pressure and water was added to the remaining methanol (1 mL) And ethyl acetate (200 mL). The organic phase is separated and washed with water, iM Na〇H solution and brine. The organic phase is dried (MgS04) and solvent is evaporated to give the product as a yellow oil. Rate: 13.2g (95 〇 / 理论 of theory) Mass Spectrum (ESI+) : m/z = 235 [M+H] +

Example VIII

(3-transiminoamino-6-methoxy-diarhydronium-1-yl)-methyl acetate was dissolved in water (4 mL) and methanol (50 mL) with stirring at reflux temperature ( 6-Methoxy-3-oxo-indoline-indole-methyl)acetate (12. g), hydroxylamine hydrochloride (4.6 g) and sodium acetate (5.5 g) for 3 h. After cooling to room temperature, water (100 mL) was added and the solution was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). Evaporation of the solvent gave the product as a brown oil. 135590.doc -96- 200927115

Yield: 12.5 g (98% of theory) Mass (ESI+): m/z=250 [M+H] Example IX

Hn^-h Η gasification of 5-methoxy-3-methoxycarbonylmethyl-diarhydron-1-yl-ammonium oxime at room temperature under a hydrogen atmosphere with 10% palladium on carbon (3.0 g) A mixture of (3-hydroxyimino-6-nonyloxy-dihydroindol-1-yl)-acetic acid f ester (12.5 g) and concentrated hydrochloric acid (4.7 mL) in methanol (150 mL) overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dried with aq. EtOAc (EtOAc) elute Yield: 13.0 g (theoretical value of ι 〇〇〇 /0) mass spectrum (ESI+): m/z=236 [M+H]+ (amine)

Example X

HNh Η gasification of 3-carboxyindolyl-5-methoxy-diargon-1-yl-ammonium by stirring in a solution of 2 hydrazine hydrochloride (120 mL) at reflux temperature Methyl lactylmethyl-two wind unloading · 1 _ group-pressing (12.5 g) for 3 135590.doc -97- 200927115 h ° then 'removing the solvent and using the toluene to dry and lend in the form of a total of Buddha It is further purified by washing with two different (four) washings. The product was dried at 5 (TC). Yield 11.1 g (1% of theory) Mass Spectrum (ESI+): m/z=220 [M+H]+ (amine)

Example XI

0 1 oxo-9·argon-bicyclo[6.3.1.0*2,7*1 twelf-2,4,6-tris--10-bright dissolved in a bite at room temperature (5〇 〇mL) gasification 3 • ruthenylmethyl _ 5 methoxy-dihydro benzyl-1-yl-ammonium (13.2 g) and 1_cyclohexyl _3_ (2 morpholinoethyl) carbonization Diimine methyl p-toluenesulfonate (21.7 for 7 d. The pyridine was then removed under reduced pressure and the residue was dissolved in water (2 mL) and di-methane (200 mL). The aqueous phase was extracted twice with dioxane. The combined organic phases were washed with EtOAc EtOAc EtOAc EtOAc. Yield: 3.0 g (29% of theory) MS (ESI+): m/z=204 [M+H] +

Example XII

135590.doc -98- 1 _methoxy-9-aza-tricyclo[6_3.1.〇*2,7*]12-2,4,6-triene 1 borane tetrahydrofuran complex (70 mL) was added dropwise to the ice bath 200927115 Cooled 4_methoxy_9_aza-tricyclo[6.3·1·〇*2,7*]12-2,4,6-triene -l〇-_(3.〇g) in THF (20 mL). The resulting solution was stirred at reflux temperature for 5 h and then stirred at room temperature overnight. The solution was cooled to about 10 c and half concentrated hydrochloric acid (5 〇 mL) was carefully added. The mixture was stirred at room temperature for 1 h and further stirred at reflux temperature for one hour. The solvent was removed and 2 μL NaOH solution (50 mL) was added to the residue. The resulting mixture was extracted with dichloromethane and dried (MgSO.sub.4). After the solvent was removed, the residue was dissolved in ethyl acetate (2 mL) and EtOAc (3 mL) Yield: 0.8 g (19 〇/〇 of theory). Mass spectrum (ESI+): m/z=i90 [M+H] +

Example XIII

HO ® Azin 4-hydroxy-9·azepine-tricyclo[6·3·1·0*2,7*] 12-2,4,6-triene is stirred under reflux 4-methoxy- 9-aza-tricyclo[6.3.1,0*2,7*]dodec-2,4,6-triene (0.50 g, oxalate) in hydrobromic acid (48% in water, 10 mL) The solution in it took 3 h. Next, the solution was concentrated under reduced pressure and the residue was dried in azeotropy using hydrazine and ethanol. The residue was washed with acetone and dried to give a crystal. Yield: 0.23 g (49% of theory) Mass Spectrum (ESI+): m/z = 176 [M+H] + (amine) 135590.doc • 99· 200927115 The following compounds are similar to the examples obtained: (1) (10), (6) Trimethyl-10-2,3,4,s,6·hexanitro-2 6-bridged benzo[d]nitrogen-9-ol

Mass Spectrometry (ESI+): m/z = 232 [M+H] + </ RTI> (2A6Q-9.

4,5,6-Hexahydro-2,6-indole-benzo[d]azepine [Tartrate, see WO 99599% (1999) for preparation) and isolated as hydrogen bromide.

Example XIV

9-Hydroxy-6,11,11-dimethyltetrahydro_4h_26 methyl bridge benzo[d] hydrazin-3-carboxylic acid tert-butyl ester hydrazine dibutyl phthalate (8.7 g) was added to 6 ,^-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[(1]azaindole-9-ol (12()§) and triethyl The solution was stirred overnight at room temperature in a solution of EtOAc (1 mL) (EtOAc). The organic extracts were combined with the organic phase. The organic phase was washed with 1 EtOAc, water and brine and then dried (MgSO.sub.4). After the solvent was removed under reduced pressure, the residue was taken from diisopropyl ether. Crystallization gave the title compound 0 Yield: 6.5 g (51% of theory) 135590.doc -100 - 200927115 Mass Spectrum (ESI+): m/z = 332 [M+H] + The following compounds are obtained analogously to Example XIV: 1) (2/?,6 magic-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3-carboxylic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 332 [M+H] + (2) (2 Λ,6β,115)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro- 4H- 2,6-anthracene-benzo[d]azepine-3-decanoic acid tert-butyl ester

(3) (25,6 and)-8-hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-411-2,6-anthracene-benzo[d Nitrogen 4-3-carboxylic acid tert-butyl ester

This compound can be obtained by analyzing a racemic mixture by palm phase HPLC. (4) (2Λ,65&gt;8-hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H- 2,6-methyl bridge-benzo[d]nitrogen Indole-3-carboxylic acid tert-butyl ester

135590.doc -101 - 200927115 This compound can be obtained by resolution of a racemic mixture by palm phase HPLC. (5) (2&amp;6/0-9-hydroxy-6,8,11,11-tetradecyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d Nitrogen 啐-3 - butyl citrate

This compound can be obtained by analyzing the racemic mixture by palm phase HPLC. (6) (2Λ,65&gt;9-hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[1] Nitrogen 4_3-carboxylic acid tert-butyl ester

This compound can be obtained by analyzing a racemic mixture by palm phase HPLC. Q 8 -hydroxyl-decyl-1,2,5,6-tetrahydro-4H-2,6-methyl-bridged benzo[d]azepine-3-decanoic acid tert-butyl ester

(8) (2 and, 65)-9·hydroxy-6,11,11-trimethyl-l,2,5,6-tetrahydro-4H2,6-methyl bridge-benzo[d]azepine- 3-carboxylic acid tert-butyl ester 135590.doc 200927115

Mass Spectrometry (ESI+): m/z = 332 [Μ +Η] + The compound can be resolved by HPLC for the palm phase phase or by using the same as in Example ΧΠΙ(1) or by The synthesis of the racemic starting material obtained by the palm phase HPlc resolution of the racemic mixture to obtain the racemic starting material is described in EP 521 422 (1993). Ο (9) 7-Hydroxy-6,11,11-trimethyltetrahydro-4H_26-methyl bridge stupid and [d]azepidine-3-carboxylic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 332 [M+H] Example XV

G trifluoro-methanesulfonic acid 3-(benzoxazol-6-carbonyl)·6-methyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzo[ d]azinium·8·yl ester Trifluoromethanesulfonic anhydride (0.77 mL) was added under argon to benzothiazole -6-yl-(8-hydroxy-6-methyl-1) cooled to -10 °C , 2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azol-4-yl)-methanone (1,24 g; see Example 92 for synthesis), triethylamine (3.4 mL) and 4-didecylaminopyridine (10 mg) in dichloromethyl 135590.doc-103-200927115 alkane (12 mL). The solution was at about _5. The crucible was stirred 3 times and then stirred overnight at room temperature. The reaction solution was added to ice-cold water and then a concentrated aqueous ammonia solution was added. The resulting mixture was extracted with EtOAc (EtOAc m.). 89% of theory) Mass Spectrum (ESI+): m/z = 495 [M+H] + The following compounds are obtained in analogy to the example XV: ® (1) (2Λ,65&lt;)_trifluoro-decanesulfonic acid 3 Benzyl·6,11,11·tridecyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge_benzo[indolizine 啐_1〇-yl ester

Mass Spectrometry (ESI+): m/z = 454 [Μ+Η] + 〇(2) 6,11,11-trimethyl_9·trifluoromethanesulfonyloxy_1,2,5,6-four Hydrogen - 4Η·2,6_曱桥-本和[d]气吟-3-曱酸三丁g

Mass Spectrum (ESI+): m/z = 464 [M+H] + (3) (2 Λ,65&gt;6,11,11-trimethyl_10-trifluoromethanesulfonyloxy_ 1,2,5 ,6_tetrahydro-4H_2,6-anthracene-benzo[nitrogen trifluoride-3_decanoic acid tert-butyl ester 135590.doc •104- 200927115

(4) (2Λ,6/〇-6,11-dimercapto-8-trifluorodecanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methyl bridge- Benzo[d]azepine-3-decanoic acid tert-butyl ester

F mass spectrometry (ESI+) : m/z = 450 [M+H] + (5) 6,11,11-tridecyl-8-trifluoromethanesulfonyloxy-1,2,5,6-tetra Hydrogen-4H-2,6-methyl bridge-benzo[d]nitro-3--3-decanoic acid tert-butyl ester

F 〇(6) (2/?,6 幻-6,11,11-tridecyl-9-trifluoromethanesulfonyloxy- 1,2,5,6-tetrahydro-4H-2,6 -methate-benzo[d]azepine-3-decanoic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 464 [M+H] + (7) (2/?, 6 and, &lt;&gt;&gt;&gt; trifluoro-decanesulfonic acid 9-cyano-6,11-dimethyl-3 - 135590.doc -105- 200927115 (2,2,2-trifluoro-ethenyl)-1,2,3,4,5,6-hexahydro-2,6-anthracene-benzo[[1 Nitrogen--8

F mass spectrometry (ESI+) : m/z = 488 [Μ+ΝΗ4] + (8)(2/?,6/?,11/〇-trifluoro-methanesulfonic acid 9-cyano-6,11-dimethyl 3-(2,2,2-trifluoro-ethenyl)-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[nitride 啐-8 -base ester

F mass spectrometry (ESI+) : m/z = 488 [Μ+ΝΗ4] + (9) 6,11,11-trimethyl-7-trifluoromethanesulfonyloxy-1,2,5,6-tetra Hydrogen-4Η-2,6-methyl bridge-benzo[d]azepine-3-carboxylic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 464 [M+H] + EXAMPLE XVI 135590.doc -106- 200927115

(2^65)-3-^ f ^-1,2,3,4,5,6-^ ^.2,6_f benzo[d]nitrogen 4-10-carbonitrile 肆(diphenylphosphine) (0) (2.79 g) was added to maintain the argon atmosphere (27?,65&gt;trifluoro-methanesulfonic acid 3-benzyl-6,11,Π_三曱基_12,3,4,5 6_ hexahydro-2,6-anthracenyl-benzo[[1]nitro-4-indole-yl ester (7.3〇§) and cyanide (285 〇g) in dimethylformamide (35 mL) The mixture was stirred at 100 ° C for 6 h. After cooling to room temperature, water (300 mL), concentrated solution (10 mL) and ethyl acetate (150 mL) The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with brine and dried (MgSO.sub.4). (R. hexane/ethyl acetate: 19:1)yield to give the product. ield: 4.43 g (yield: 620/?). Similar to the example XVI obtained: (1) (2&amp;6/M1 phantom-8-cyano-6, U dimethyl-tetrahydro _4η· 2,6-methyl bridge-benzo[d]azepine- 3-carboxylic acid third butyl vinegar

Mass Spectrum (ESI+): m/z = 327 [M+H] 135590.doc -107- 200927115 (2) 9-Cyano-6,11,11-trimethyl-1,2,5,6-tetrahydro -411-2,6-A bridge-benzo[d]azepine-3-carboxylic acid tert-butyl ester

. Mass spectra (ESI+): m/z = 341 [M+H] + (3) (2;?,65&gt;9-cyano-6,11,11-tridecyl-1,2,5,6- Tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3-carboxylic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 341 [M+H] + (4) 7-Cyano-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6 -methate benzo[d]azepine-3-carboxylic acid tert-butyl ester

Mass Spectrum (ESI+) ·· m/z=341 [M+H] + Example XVII

135590.doc -108· 200927115 (2Λ,6Α·3-benzyl_6,U,11-trimethyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzene And [d]azetium-i〇-ethyl formate (2Λ,65&gt;3-benzyl-6,11,11-trimethyl-l,2,3,4,5,6-hexahydro-2 , 6-A bridge _ benzo[d]azepine-10-carbonitrile (1.14g) in 80. / o sulfuric acid (4mL) solution was stirred at 150 ° C for 1 h. After cooling to room temperature, add Ethanol (3 〇 mL) and the solution was stirred for 2 d at 100 C. Then, the cooled solution was added to water (100 mL) and the mixture was basified with 40% aqueous NaOH. Dry (MgS 〇 4). The solvent was removed under reduced pressure to give the crude product. Yield: 1.14 g (87% of theory) Mass. (ESI+): m/z = 378 [M+H] + Similar to Example XVII, it was obtained: (1) 6,11,11-trimethyl_ι,2,3,4,5,6-hexahydro-2,6_methyl bridge-benzo[d]nitrogen 4-9- Ethyl citrate

Mass Spectrometry (ESI+): m/z = 288 [M+H] + </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Preparation of 9-carbonitrile. (2) (2Λ,6Λ,115&gt;3-(3Η-benzimidazole_5_carbonyl)didiyl-1,2,3,4,5,6-hexahydro-2,6-anthracene-benzene And [Ammonia 啐8_ decanoic acid ethyl ester 135590.doc •109· 200927115

Mass Spectrometry (ESI+): m/z = 274 [M+H] + The compound was applied from (2 Λ,6/?,Π5*)-6,11-dimethyl. 1,2,3,4, Preparation of 5,6-hexahydro-2,6-methyl bridge-benzo[(1]nitrogen_8-carbonitrile. (3)1·hydroxy-8-methoxy·3_methyl·2,3 ,4,5-tetrahydro-_ιη-2,6-anthracene-benzo[d]azepine-6-decanoate

The compound can be used as described above to replace ethanol with hydroxy-8-methoxy-3-methyl-2,3,4,5·tetrahydro-1 Η·2,6-methyl bridge-benzo[d]. Nitrogen broken winter armor [about synthesis, see US 3687957 (1972)] preparation.

Example XVIII

〇

Methyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzo[d](2^,65)-6,11,11-three gasaki-10-carboxylic acid E-box adds Pd(OH)2 (0.20 g) to (10), called 3_jieji_6 ιι ιι•三methyl_1,2,3,4,5'6·hexahydro·2,6·A Bridge _benzo[d]azepine]indole-formic acid ethyl ester 135590.doc -110· 200927115 (lU g) in a solution of ethanol (2 〇 mL). The resulting mixture was stirred overnight under a hydrogen atmosphere (5 psi) at room temperature. Next, the catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to give a product. Yield: 0.61 g (71% of theory) Mass (ESI+): m/z = 288 [M+H] + The following compound was obtained similar to Example XVIII: (1) (2Λ,65&gt;6,11, 11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine-10-carbonitrile

Show diastereoisomers racemic mixture)

(3) 5,6,7,8,9,10-hexahydro^^❹-methyl bridge-acridine and ^di-azide oxime to the diastereomers racemic mixture

Mass Spectrum (ESI+): m/z = 175 [M+H] + Debenzylation was carried out as described above in the presence of 1 equivalent of 1 hydrazine hydrochloric acid. (4) 4-mercapto-3,5,9-triaza-tricyclic [6.3.10^61+:-2(6),4-135590.doc -111 - 200927115 dilute Isomerization racemic mixture)

Mass Spectrum (ESI+): m/z = 178 [M+H] Example XIX

❹ 6,11,11-trimethyl-9-phenyl-1,2,5,6-tetra-argon·4Η-2,6-methyl bridge-benzo[d] hydrazin-3-carboxylic acid tertidine The ester is added to a 2 M NaaCO 3 aqueous solution (5 mL) under an argon atmosphere to 6, ιι, ι 曱 曱 _ _9- 二 曱 - 绩 绩 绩 绩 绩 绩 绩 绩 绩 - i, 2,5,6-tetrahydro _ 4Η·2,6-A bridge · Benzo[Azide 碲-3-decanoic acid tert-butyl ester (1.〇〇8) and stupid base acid (〇34 phantom in dimethylformamide (5 mL) In the mixture, the resulting mixture was flushed with argon and then 1,1,-bis(diphenylphosphino)ferrocene-di-p-palladium („) bis-chloromethane complex (0.18 g) was added. The mixture was heated to 100 ° C and stirred at this temperature for 4 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgS04) and under reduced pressure The solvent was removed. The residue was purified mjjjjjjjjjjjj ESI+) : m/z = 392 [M+H] + The following compounds are obtained in analogy to the example XIX: 135590.doc -112- 200927115 (1) (2/?, 6 feet 115 &gt; 6,1 1-Dimethyl-8-phenyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine-3-furic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 378 [M+H] + (2) (2/?,6iUl*S)-6,ll-dimethyl-8-pyridin-3-yl-1,2,5 ,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine_3_decanoic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 379 [M+H] + (3) (2i?,6iU15&gt;6,ll-didecyl-8-pyridin-4-yl-1,2,5,6-tetra Hydrogen-4仏2,6-曱 bridge-benzo[nitride 4-3-decanoic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 379 [M+H] + (4) (2/?, 6 Foot 115&gt;6,11-Dimethyl-8-pyrimidin-5-yl-1,2,5, 6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine-3-carboxylic acid tert-butyl ester

135590.doc -113- 200927115 Mass Spectrum (ESI+): m/z=380 [M+H] + (5) 6,ll,ll-trimethyl·7_pyridine_3_yl-ns/tetrahydro_4H26 A bridge-benzo[d]azepine-3-decanoic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 393 [M+HJ + ❹ Example XX

Trimethyl-tert-phenylphenylhexahydro 26-methane benzo (4) aziridine added trifluoroacetic acid (0.5 mL) to 6,ll n_trimethyl_9_phenyl·Ο 1,2,5,6·4 Hydrogen-4H-2,6-methyl bridge-benzo[d]azepine-3-carboxylic acid tert-butyl ester (0.30 g) in a solution of di-methane (25). The solution was stirred at ambient temperature for 1 h and concentrated under reduced pressure. The crude trifluoroacetate salt of the title compound was used without further purification. Yield·· 0.31 g (theoretical ι〇〇〇/〇) The following compounds were obtained analogously to Example XX: (or, in the case of insufficient purity of the product after application of the procedure as described above), by reverse phase HPLC (MeCN/ Water) purified compound to obtain pure compound) 135590.doc •114· 200927115 U) (2i?,6i?,l 1^-6,11-dimethyl-1,2,3,4,5,6-hexahydrogen -2,6-曱 bridge benzo[d]azaki_8_carbonitrile

Mass Spectrum (ESI+): m/z = 227 [M+H] +. ❹ (2) 6,11,11_trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-stupid [4]aza -9-carbonitrile

Mass Spectrum (ESI+): m/z = 241 [M+H] +. ❹ (3) (2 points, 65 &gt; 6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine- 10-based amine NH,

Mass Spectrum (ESI+): m/z = 231 [M+H] +. (4) 6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[1]釓

°f-9-ylamine h2n 135590.doc • 115- 200927115 Mass Spectrum (ESI+): m/z = 231 [M+H] + This compound was obtained as the bis trifluoroacetate salt. (5) (2 eve, 6 and)-8-methoxy-6,9,11,11-tetramethyl-1,2,3,4,5,6-hexahydro·2,6·A bridge -benzo[d]nitrogen 4

The compound can be resolved by resolution of the racemic mixture by palmar phase HPLC or by using enantiomerically pure (2S,6R)-8-methoxy·6,9,11,1 tetradecyl-1 2,5,6-Tetrahydro-4Η-2,6-methyl bridge-benzo[d]azepine-3-carboxylic acid terpene vinegar. (6) (2Λ,65)_8·methoxy_6,9,11,11·tetramethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo [d]nitrogen

The compound can be resolved by chiral phase HPLC or by enantiomerically pure (2^6S&gt;8-methoxy^bi-tetram-I,2,5,6 - Tetrahydro-methyl bridge-benzo[d]azetidinecarboxylic acid tert-butyl ester obtained. (7)(10),6;?) Winter oxime 7^(1) tetramethylammonium^^-hexahydro-2,6-methine bridge -benzo[d]azepine

135590.doc -116- 200927115 The compound can be resolved by resolution of the racemic mixture by palmar phase HPLC or by the use of enantiomerically pure methoxy 1,2,5'6-tetrahydro-4 _2, 6-A bridge-benzo[[1]azepine_3_carboxylic acid tert-butyl ester obtained (8) (2/?,6*S&gt;9-methoxy_6,8,11,11_four Base 4,2,3,4,5,6-hexahydro-2,6-曱 bridge&quot;·本和[d]吟

The compound can be resolved by treating the racemic mixture with the palm phase HPlc or by using enantiomerically pure (2Λ,65&gt;9_methoxy_6,8,n,U-tetramethyl-1,2 , 5,6-tetrakis-4H-2,6-methyl bridge-benzo[d]azepine-3-carboxylic acid dibutyl® oxime. (9) 8,9-dimethoxy_6,11 , 11_triterpene-1,23,4,5,6_hexahydro-2,6-methyl bridge·benzo[d] gas

(10) 8-methoxy bridge

Methoxy-6,11,11-trimethylidene-1,2,3,4,5,6-hexahydro-2,6-methyl(1^9_methoxy_6,11,11-trimethyl Base _i,2,3,4,5,6-hexahydro-2,6_甲135590.doc 117- 200927115 Bridge-benzo[d]nitrogen 4-8-ol

(12) (2i^,65&gt;6,ll,ll-trimethyl-l,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]nitrogen-9 -carbonitrile

Mass Spectrum (ESI+): m/z = 241 [M+H] +. (13) (2*S,6i〇-9-methoxy-6,ll,ll-trimethyl-l,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzene And [d] nitrogen peak

This compound can be obtained from a racemic mixture by separating the enantiomers by palm phase HPLC. (14) (2i?,6iUl*S)-6,ll-dimethyl-8-phenyl-1,2,3,4,5,6-hexahydro-2,6-anthracene-benzo[ d] nitrogen 4

Mass Spectrum (ESI+): m/z = 278 [M+H] + 135590.doc -118 - 200927115 (15) (2 and 6 Foot 115&gt;6,11-Dimethyl-8-pyridin-3-yl- 1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine

Mass Spectrometry (ESI+): m/z = 279 [M+H] + (16) (2/?, 6-foot 11*S)-6,11-didecyl-8-pyridin-4-yl-1,2 ,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine

Mass Spectrometry (ESI+): m/z = 279 [M+H] + (17) (2,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4,5,6-hexahydro-2,6-anthracene-benzo[d]nitrogen 4

Mass Spectrum (ESI+): m/z = 280 [M+H] + (18) 6,11,11-trimethyl-7-pyridin-3-yl-1,2,3,4,5,6-six Hydrogen-2,6-methyl bridge-benzo[d]nitrogen

135590.doc -119· 200927115 Mass Spectrum (ESI+) : m/z=293 [M+H] + (19) 6,11,11-trimethyl-1,2,3,4,5,6-hexahydro -2,6-A bridge-stupid [d] Nitrogen-7-A guess

Mass Spectrum (ESI+): m/z = 241 [M+H] + EXAMPLE XXI HO. 〇

(2Λ,65)_(3·benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzo[d]nitrogen啐_10_基)-Formaldehyde (2Λ,65)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-曱Band-benzo[d]azepine-10-carboxylic acid ethyl ester (0.96 g) in tetrahydrofuran (2 mL) hydrazine was added dropwise to LiAlH4 in tetrahydrofuran (1.5 mL) (1,6 mL '2.4 mol /L in THF). The reaction mixture was stirred at ambient temperature for 90 min. Water (4 mL) was then carefully added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSCn). The solvent was removed under reduced pressure to give the product. Yield: 0.62 g (72% of theory) Mass (ESI+): m/z = 336 [M+H] +

Example XXII 135590.doc -120- 200927115

(2 and, 6*5)-6,10,11,11·tetramethyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzo[W azepine 10% palladium/carbon (0.10 g) was added to (2 and 6 pheno-(3-benzyl-6,11,11-trimethyl-1'2,3,4,5,6-hexahydro-2 , 6-A bridge-benzo[d]azepine-1〇-yl)-methanol (〇·60 g) in a solution of methanol (10 mL) at room temperature in a hydrogen atmosphere (5 〇 psi) The mixture was stirred overnight. Then, another portion of 丨〇% palladium/carbon (0.2 g) and 4 Μ hydrochloric acid (1 mL) was added and the mixture was stirred under hydrogen atmosphere for 4 h. After separation of the catalyst by filtration, under reduced pressure The filtrate was concentrated to give the hydrochloride salt of the title product. Yield: 0.50 g (100 理论 〇 理论 〇 〇 〇 〇 〇 〇 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下 以下3,4,5_tetrahydro-1112,6-methyl bridge_benzo[Nitrite-6-carboxylic acid decyl ester

The above procedure can be carried out by the above procedure from hydrazine-hydroxy-8-methoxy-3-indolyl-. ',, tetrahydro-1H-2,6-methyl bridge-benzo[d]azepine_6-formic acid methyl ester was obtained. S-reduction can be performed similar to 汄GW 1987, 52, 5233-5239.

Example XXIII 135590.doc -121- 200927115

ο(2 and 65)-10-amino-6,11,11-trimethyl-1,2,5,6-tetraki-4Η-2,6-methyl bridge·benzo[d]nitrogen第三-3-carboxylic acid tert-butyl ester will be equipped with a stir bar, (2Λ,6^-6,11,11-trimethyl-10-trifluoromethylpyridinyloxy-1,2,5,6 - tetrahydro-4Η-2,6-methyl bridge-benzo[d]azepine_3_carboxylic acid tert-butyl ester (4.0 g), dibenzylideneamine (3.2 mL), Cs2C〇3 (5.6 and The toluene (80 mL) flask was flushed with argon for 1 2 min. Then 2,2'-bis-di-^-diphenylphosphanyl-[l,1']binaphthalene (0.35 g) and ginseng were added. (Dibenzylideneacetone) dipalladium (0.18 g) and the resulting mixture was stirred at reflux temperature. After cooling to room temperature, the reaction mixture was washed with water and concentrated. The residue was dissolved in tetrahydrofuran and added 2 Μ Hydrochloric acid. The mixture was stirred at ambient temperature for 4 h. The precipitate was separated by filtration and the residue was evaporated. Product: 产率 Yield 0.83 g (29% of theory) Mass Spectrum (ESI+): m/z = 331 [M+H] + The following compounds are similar to Example XXIII Obtained: (1) 9-Amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-411-2,6-methyl bridge_stupid[d]azepine-3- Tert-butyl formate

Mass Spectrum (ESI+): m/z = 331 [M+H] 135590.doc -122- 200927115 tetrahydro-4H-2,6-methyl bridge-benzene

(2) 8-Amino-6,11,11-trimethyl-[d]azepine-3-carboxylic acid tert-butyl ester

Mass Spectrum (ESI+): m/z = 331 [M+H] + EXAMPLE XXIV

Methyl-1,2,3,4,S,6-hexa-argon-2,6-methyl bridge_(2/?,6»5)-1()-gas-6,11,11·tribenzo [d] Nitrogen strontium A solution of nitrosonium tetrafluoroborate (0.25 g) in - „r焓r〇τ, + ---'&quot; alkane (2 mL) is added to (10), which is called 1 〇-amino group. a solution of -HH·trimethyl 12,^ four gas_4H26_methyl bridge-benzo[d]azepine-3-carboxylic acid tert-butyl ester (〇.1〇g) in dioxane (2 mL) The solution was heated to 5 (TC and stirred at this temperature overnight. The © reaction solution was diluted with decyl alcohol and then concentrated under reduced pressure. To reverse the album 1 ^ 0: () \ 46 〇 ^ / 112 〇 The residue was purified to give the title product. Yield: 25 mg (yield: 36% of theory) Mass (ESI+): m/z = 234 [M+H] + Similar to Example XXIV: (1) 8-Fluoro-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge_benzo[d] Nitrogen fluoride 135590.doc -123 - 200927115

(2) 9-fluoro-6,11,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6_methyl bridge-benzo[d]aza

The crude product was treated with trifluoroacetic acid in dioxane in the absence of complete cleavage of the second butoxyl group after the reaction.

Example XXV

8,9_dimethyl-6,11,11-trimethyl-1,2,5,6-tetraar-_411-2,6-methyl bridge-benzo[d]azepine-3-carboxylic acid Tributyl ester adds ditributyl dicarbonate (0.34 g) to 61111_trimethyl_© 1,2,3,4,5'6-hexahydro-2,6-methyl bridge-benzo[〇 1] A solution of nitrogen 14_8,9-diol (〇.44 §) and diethylamine (0.43 mL) in dioxane (5 mL). The solution was stirred for 2 h at room temperature. The solution was then washed twice with water and once with brine. After drying (MgSCU), the solvent was removed under reduced pressure to give a product. Yield: 0.43 g (80% of theory)

Mass Spectrum (ESI·): m/z = 346 [M-H] - Example XXVI 135590.doc -124- 200927115

8,9-Methylenedioxy_61111 trimethyl 1 2 5 6 tetra gas 4h 2 6 methyl bridge-benzo[d]azepine·3_carboxylic acid tert-butyl ester 8,9-dihydroxy group 6,u,u_trimethyl_1 2 5 6 tetrahydro_4Η 2,6-methyl bridge_benzo[d]·azepine-3-decanoic acid tert-butyl ester (0 21 g), K2C〇3 (〇19 g) and a mixture of diiodomethane (54 μL in dimercaptocaramine (5 mL) were heated to 100 C and stirred at this temperature for 2 h. Next, another portion of diiodoguanidine was added. (54 μ!^Κ2(:03(〇·18 g) and then after mixing 5% under TC to cool to room temperature, add water and extract the mixture with ethyl acetate. The combined organic The extract was washed with brine and dried (MgSO.sub.4). After the solvent was removed, the residue was purified by EtOAc (EtOAc EtOAc (EtOAc) Mass Spectrum (ESI+): m/z = 360 [M+H] +

Example XXVII

Μ-Methylenedioxy-6,11,11-trimethyl+2 3 4 5 6 hexahydrate 2 6-methyl bridge-benzoxanthene d]nitrogen 4 ' Hydrochloric acid containing isopropanol (5 mol/ L, 0.55 mL) was added to 8,9-methylenedioxy-6,llu trimethyl 1,2,5,6-tetrahydro-4H-2 dissolved in dichloromethane (2 mL). 6-A bridge-benzo[d]azepine_3·carboxylic acid tert-butyl ester (0.19). The resulting solution was stirred at room temperature for 2 h. Next, the solution was concentrated under reduced pressure 135590.doc -125 - 200927115 to give the title compound as the hydrochloride salt. Yield: 0.15 g (97% of theory) Mass (ESI+): m/z = 260 [M+H] +

Example XXVIII

OH 2-(2-decyloxy-nodoxy)-3,3-dimethyl·Brigade-4-ol Add sodium borohydride (0.31 g) to 2- dissolved in methanol (20 mL) (2-decyloxy-benzyl)-3,3-dimercapto-piperidin-4-one (2.00 g, prepared from a racemic starting material according to J. Mei CTzew. 2002, 45, 3755-3765 ). The solution was stirred at room temperature for 3 h and then 1 NaOH solution (40 mL) was added. After stirring for 10 min, the mixture was extracted with dioxane. The combined organic extracts were washed with water and dried (MgSO4). Evaporation of the solvent gave the title product. Yield: 2.00 g (99% of theory) Mass (ESI+): m/z =250 [M+H] +

Example XXIX

10-methoxydimethyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzo[d] hydrazine 135590.doc -126- 200927115 Μ-methoxy The solution of _3,3-dimethyl kappa 4-alcohol (〇8 〇 多 in polycarboxylic acid (Η) mL) was mixed overnight under (10). After the solution was cooled to about 'c, water (300 mL) was added and the mixture was vigorously stirred again. Next, the mixture was cooled in an ice bath, more water was added, and the mixture was purified using an aqueous solution of ι〇 Μ Na〇H. The mixture was extracted with acetic acid and the combined organic extracts were washed with brine and dried (MgSO.sub.4). The solvent was removed under reduced pressure to give the title product which was used without further purification.

Yield: 36.36 g (49% of theory) The following compound was obtained from the compound XXIX: (1) (2S,6i?)-9-methoxy-6,11,11-trimethyl-1, 2,3,4,5,6-hexahydro_ 2,6-methyl bridge-benzo[[1]nitrogen 4

The racemic product mixture was resolved to its enantiomer by using palmar phase HPLC. Compounds can also be obtained analogously to the procedure described in 乂 C/zew. 1997, ct., 2922-2930.

Instance XXX

135590.doc -127 200927115 4_(2,6-Dimethyl-morpholine_4_ylmethyl)benzamide ^acid (〇·34 mL), formic acid trimethyl (tetra) 〇66 and triethyl ethoxylate The hydrogenated naphthalene (0.53 g) was sequentially added to f-mercaptobenzoic acid (15 mg) and 2,6-dimethylmorpholine (1)5 dissolved in dimethylamine (3). The solution was stirred overnight at room temperature. Tri-acetic acid (5 〇% in water) was added. The solution was stirred for a further 2 h and then concentrated under reduced pressure.产率 Yield: 199 11^(550/〇 of theory) Mass Spectrum (ESI+): m/z=250 [M+H] + The following compounds are similar to the examples obtained: (1) 4-(4-hydroxy_ 4·methyl-piperidine_ι_ylmethylbenzoic acid

0H ❹ Mass Spectrum (ESI+): m/z = 250 [M+H] + This compound was isolated as the trifluoroacetate salt. (2) Inner-4-(3_hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-stupic acid

OH mass spectrum (ESI+): m/z = 262 [M+H] + This compound was isolated as the trifluoroacetate salt. 135590.doc • 128 · 200927115 (3) 4-(3 - thiol- sigma-butyl-1-ylindenyl)-benzoic acid

ΟΗ Mass Spectrum (ESI+): m/z = 208 [Μ+Η] + This compound was isolated as the trifluoroacetate salt. (4) 4-(3-Hydroxy-pyrrolidin-1-ylmethyl)-benzoic acid

ΟΗ Mass Spectrum (ESI+): m/z = 221 [Μ+Η] + This compound was isolated as the trifluoroacetate salt. (5) 4-(4-Methoxy-Pydidine-1-ylmethyl)-benzoic acid

Mass Spectrum (ESI+): m/z = 250 [ Μ + Η] + This compound was isolated as the trifluoroacetate salt. (6) 4-(4-Hydroxy-piperidin-1-ylindenyl)-benzoic acid 135590.doc -129- 200927115

Mass Spectrum (ESI+): m/z = 236 [M+H] +

OH

This compound is isolated as its trifluoroacetate salt. Example XXXI

❹ (2 and, 6*5)-6,11,11-dimethyl·1,2,3,4,5,6-hexaquinone-2,6-methyl bridge-benzo[d]nitrogen 4 10% Pd/C (0.20 g) was added to (2R,6S)-trifluoromethanesulfonic acid 3_benzyl-6'11,11-trimethyl-1,2,3,4,5,6-six Hydrogen 2,6-methyl bridge benzodiazepine 10-carboxylate (0.50 g) in ethanol (10 mL). The resulting mixture was shaken overnight at room temperature under a nitrogen atmosphere (50 psi). The catalyst was then separated by separation and Pd(OH)2 (0.2 g) was added to the filtrate (the benzyl group was not completely removed after cleavage in the presence of pd/c). The mixture was again shaken under a hydrogen atmosphere (50 psi) for 16 h at room temperature. The catalyst was isolated and the filtrate was concentrated under reduced pressure to give crude material. The crude product was used without further purification. Yield: 0.23 g (98% of theory) The following compound was obtained similar to Example XXXI: (1) 3,5,9-triaza-tricyclo[6.3.1.0*2,6*]12-2 (6), 4-diuret (racemic mixture of diastereomers shown) 135590.doc -130- 200927115

Example XXXII

(2/?,6*5)-2,2,2-trifluoro-1-(10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetraar- 4H-2 ,6-A bridge-benzo[d]nitro 4-3-yl)-ethanone

三氟 Add trifluoroacetic anhydride (5.0 mL) to the ice bath to cool (2Λ,65&gt; 6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6 - a solution of a bridge of benzo[d]azepine-indole-alcohol hydrobromide (5.0 g) and triethylamine (5.5 mL) in dichloromethane (50 mL) at ambient temperature The resulting solution was stirred overnight. Then water was added and the mixture was stirred for 15 min and the organic phase was separated. The organic phase was washed with water and brine, dried (Nk.丨: 4) Purification of the residue gave a product as a foamy solid. Yield: 3.34 g (64 理论 〇 理论 〇 质谱 质谱 质谱 ESI ESI ESI ESI 328 328 328 328 328 328 328 328 328 328 328 328 328 328 328 328 328 Example XXXII obtained: (1) (State 岣-2,2,2_trifluoromethane (6,u,u_trimethyl_12,5 6 four gas_ 4H-2,6-曱 bridge_benzo[d] Nitrogen 吟_3_基)_乙鲷

135590.doc -131 - 200927115 ❹ Mass Spectrum (ESI+): m/z=312 [M+H] + (2) (2;?,6Λ,115)-2,2,2-Trifluoro 1,2,5 ,6-tetrahydro-(8. hydroxy 4Η-2,6-methyl bridge-benzo[d]azepine-3-yl)6'lK dimercapto

Mass Spectrometry (ESI+) : m/z = 3 14 [Μ+Η] + (3) (2 and, 6iUli?)-2,2,2-trifluoro-1-(8_叙# hydroxy·6ΐ1 1,2 ,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]azepine)-methylethyl 1

Mass Spectrum (ESI+): m/z = 314 [M+H] + Methyl-(4) (27^,65)-2,2,2-trifluoro-1·(9-urethyl_6 lj ^ 1 , 2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen_3·yl)_acetoxime HO,

G ο

Example XXXIII ο

F (2Λ,65&gt;2,2,2-trifluoro-1-(10-hydroxy-6,11,11-trimethyl-9-nitro-1,2,S,6·tetra-argon-4Η- 2,6-A bridge-benzo[d]nitro 4-3_yl)-ethanone slowly added nitric acid (0.4 mL) to the ice bath (2 van 6 &lt; 5) - 135590.doc • 132 - 200927115 2'2'2--fluoro-1-(10-carbyl-6,11,11-trimethyl-4,2,5,6-tetrahydro-411-2,6-methyl bridge-stupid [d] A solution of indole-3-yl)-ethanone (2.9 g) in acetic acid (5 mL). The ice bath was removed and the solution was stirred overnight at ambient temperature. The solution was poured into ice-cold water with acetic acid The resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (Na2SO4). &gt; 1:3) Purification residue Yield: 1.3 g (39% of theory) © MS (ESI): m/z=:::::::::::::: 2,2,2-trifluoro-1 -[(2/?,6Λ,1 l&lt;S)-8-ylamino-6,11-dimethyl-9-definite-1,2,5, 6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azepin-3-yl]-ethanone

Mass Spectrum (ESI+): m/z = 359 [M+H] + (2) 2,2,2·trifluoro·1-[(2π,6/Μα)-8-hydroxy-6,11-dimethyl _7_Nitro-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]azepin-3-yl]-ethyl

〇0 mass spectrometry (ESI+): m/z = 359 [M+H] + This compound was obtained as a mixture of the compound ΧΧΧΙΠ(1) 135590.doc -133- 200927115, which is obtained by the mixture &amp; Separated by chromatography as described above. Base-8 nitrate (3) 2'2,2·trifluorohydroxy-6,11,11-trimethyl·1,2,5,6-tetrahydro·4Η_2 6 ψ bridge benzo[d] nitrogen peak _ 3 Kib

Mass Spectrum (ESI+): m/z = 373 [M+H] +

F F ❹ This compound was obtained by a mixture with a compound example (4), which was separated by chromatography as described above. /(4) 2,2'2-trifluorohydroxy_6, U11_ three in ·-丨0-Shi Xiaoji-1,2,5,6-tetrahydro·4η_2,6_曱 bridge_benzo[d] Nitrogen 啐_3_基]_乙鲷

Mass spectrum (ESI+): m/z = 373 [M+H] + ❹ The compound was obtained as a mixture with the compound ΧΧΧΠΙ(3). The mixture was separated by chromatography as described above.

Example XXXIV \\ ο

F (2/?,615)-2,2,2-trifluoro_1_(1〇_methoxy_6,11,11-trimethyl-9nitro 1,2,5,6-tetrachloro _4H-2,6-A bridge-benzo[d]azin-3-yl)·acetamidine I35590.doc -134- 200927115 Add iodocarbazide (8〇μΧ) to (10), fluorine is small (ι〇 • via base MW-trimethyl-9_nitro-cutting tetrahydro-specific 26 • methyl bridge benzo (4) nitrogen 4-3-yl)-ethanone ((Mo g) and carbonic acid unloading (〇 17 g) in two In a mixture of methyl amide (5 mL), mix the mixture overnight at room temperature, then add another: part of methyl iodide (8 〇 (4) and potassium carbonate (〇16 illusion. Mix the mixture at the moment) After 6 h, water and ethyl acetate were added, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and dried (Na.sub.2.sub.4). It was used without further purification. Yield: 0.41 g (1 〇〇 〇 理论 理论 〇 〇 〇 〇 质谱 质谱 质谱 质谱 质谱 M M M M M M M M M M M M 以下 以下 以下1) (2ι5,6Λ)-8-methoxy-6,9,11,11_tetramethyl-1,2,5,6_ four wind-4Η- 2,6_曱 bridge·benzo[d] Nitrogen-3-carboxylic acid Tributyl ester

The compound can be resolved by chiral phase HPLC to resolve the racemic mixture or by using enantiomerically pure (2&lt;S,6i〇-8-hydroxy-6,9,11,11-tetradecyl-1) 2'5,6-tetrahydro-4H_2,6-methyl bridge-benzo[d]nitrogen 4-3-decanoic acid tert-butyl ester. (2) (2i?,6lS&lt;)-8-methoxy -6,9,11,11-tetramethyl-1,2,5,6·tetrahydro·4Η· 2,6-曱 bridge-benzo[d]azepine_3_carboxylic acid tert-butyl ester 135590. Doc -135· 200927115

The compound can be obtained by aligning the palmar phase with 11 wells (: parsing the racemic mixture or by using enantiomerically pure (2i?, 6jS)_8_hydroxy 6,9,^,^ tetramethyl, 1,2 , 5,6·tetrahydro-4H-2,6-anthracenyl-benzo[d]azepine_3•tributyl carboxylic acid obtained. (3) (25^6/^)-9-methoxy _6,8,11,11_tetramethyl_i,2,5,6-tetrahydro_4 _ ❹ 2,6-methyl bridge-benzo[d]azaindole_3_decanoic acid third ester

The compound can be resolved by treating the racemic mixture with the palm phase Hplc or by using enantiomerically pure (25,6/^)-9-carbyl-6,8,11,1 tetramethyl-1 '2,5'6-tetrahydro-411-2,6-methyl bridge-benzo[[1]nitrogen-4-3-carboxylic acid tert-butyl ester obtained. ❹ (4) (2/?'6&lt;S) -9-methoxy_6,8,11,11-tetradecyl-1,2,5,6-tetrahydro_4H_ 2,6-anthracene-benzo[d]azepine_3_decanoic acid Third butyl ester

The compound can be resolved by resolution of the racemic mixture by palmar phase HPLC or by using enantiomerically pure (2R,6S)-9-hydroxy-6,8,11,11-tetramethyl-1,2, 5,6-tetrahydro-41^2,6_曱 bridge-benzo[[1;|azepine-3-carboxylic acid tert-butyl ester. 135590.doc 136- 200927115 (5) 8'9-dimethyl Oxygen-6,n,u_trimethyl_1 2 5 6 tetrahydroanthracene]/·methate·benzo[d]azepine-3-decanoic acid tert-butyl ester

Methyl iodide and potassium carbonate in an amount twice the amount specified above are 8,9-dihydroxy-6,U,11-trimethyl-1,2,5,6·tetrahydro-4H-2,6- This compound was prepared by anthracycline-benzo[d]azepine_3_carboxylic acid tert-butyl ester. ® (6) 9_ 经基_8•methoxy_61111 trimethyl_12,56 tetranitro 2,6-methyl bridge-benzo[d]nitro 4-3-decanoic acid tert-butyl ester

The compound is composed of M-dihydroxy-6,llu_tridecyl_1 2 5 6 tetrahydro 4H 2,6-methyl bridge benzo (4) nitrogen _3_carboxylic acid tertidine g and (d) _9_methoxytrimethyltetrahydro-indole bridge-benzo(4)azinium-3-carboxylic acid tert-butyl ester and 8,9-dimethoxy-6,u,u•tridecyl·f'5 , 6·tetrahydro·4Η·2,6·methicone [dm 4 _3·carboxylic acid terpene vinegar as a compound form, the mixture can be separated by reverse phase HpLC. (7) 8-hydroxy-9-methoxy_6,llu trimethyl_12,56_tetrahydroanthracene 2,6-methyl bridge-benzo[d]azepine_3_carboxylic acid tert-butyl ester

135590.doc -137- 200927115 This compound is composed of 8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetraqi_ 4H-2,6-anthracene-benzo [d] N-butyl hydrazine-3-decanoate with 9-hydroxy-8-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2 ,6-A bridge-benzo[d]azepine-3-carboxylic acid tert-butyl ester and 8,9-dimethoxy-6,11,11-tridecyl _ 1,2,5,6·4 Obtained as a mixture of nitrogen-4H-2,6-methyl bridge-benzo[d]azaindole-3-decanoic acid terpene vinegar, which mixture can be separated by reverse phase HPLC. (8) 9-decyloxy-6,11,11-trimethyl-l,2,3,4,5,6-hexahydro-2,6-曱 bridge-n-[d]aza

❹ (9) (25^6/0-9-decyloxy-6,11,11·trisyl)_12,3,4,5 6 hexahydro 2,6-methyl bridge-benzo[d]nitrogen吟

Q This compound can be obtained from the racemic mixture by the palm phase HpLC. (10) 2,2,2-three gas-1-[(2/?,67Μΐ5·)-8_methoxy_611_dimethylnitro-1,2,5,6-tetrahydro_4Η_2, 6-曱桥-笨笨[d]咔咔_3_ ketone ov/

F mass spectrometry (ESI+) : m/z = 373 [M+H] + (11) 2,2'2-three gas-i_[(2 brother 6/?,115&gt;8-methoxy_6 u_2 Methyl _7 135590.doc •138· 200927115 Nitro-1,2,5,6-tetrahydro-4H-2,6-A bridge-stupid [d]aza 啐3_ 旯土二

Mass Spectrum (ESI+): m/z = 373 [M+H] + Instance XXXV

〇l-[(2/?,6S)-l〇- benzylamino-6,11,11-trimethyl_9_definite 4 '乂, four gas _4H-2,6-methyl bridge- Benzo[d]azepin-3-yl]_2,2,2·trifluoro-"2,2,2-trifluoro-l-[(2e,6&lt;S)-10-methoxy] 6,11,ΐι·三甲| τ % -9-Shi Xiaoji-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen_3_yl]•B (g) Combine with benzylamine (0.7 mL) and stir the mixture at 70 ° C overnight. After cooling to room temperature, the mixture was purified by reverse phase HPLC (MeCN/H.sup./TFA) to give an oil. Yield: 0.19 g (38% of theory). Mass (ESI+): m/z = 462 [M+H] + The following compounds are obtained in the form of XXXV: (1) 1-[(2/?,6/ ?,115)-8-benzylamino group _6, ιι_ dimethyl _9_ nitro-1,2,5,6-tetrahydro-4^1-2,6_methyl bridge_benzo[[1 Nitrogen 啐_3_yl]_2,2,2-trifluoro-ethyl 135590.doc -139- 200927115

The reaction mixture was stirred at 1 70 ° C for 5 h. Instance XXXVI

(5 and 95)-4,5,6,7,8,9-hexa-argon_9,12,12-trimethyl-5,9-methyl bridge-111-imidazo[5,4_〗] 3] Benzodiazepine 4 Stirring Nie (〇.ig), 1_[(2/?,6*S)-10-benzylamino group_6,11,11- in a hydrogen atmosphere at 50 ° C Trimethyl_9·nitro-12,5,6-tetrahydro-4Η-2,6·曱 bridge-benzo[d]azepin-3-yl]-2,2,2-trifluoro-B A mixture of ketone (0.19 g) and formic acid (10 mL) was taken overnight. The catalyst was then separated by filtration and the filtrate was concentrated. The remaining material was dissolved in decyl alcohol (1 mL) at 50. (: treated with 4 Μ 〇Na0H solution (2 mL) overnight. After cooling to room temperature, the solution was neutralized with 2 Μ hydrochloric acid and solvent was removed. The residue was purified by reverse phase HPLC (MeCN/H20). : 35 mg (33% of theory) The following compounds are obtained in analogy to the example XXXVI: (1) (6/U0i?,125&gt;5,6,7,8,9,10-hexahydro-10,12-II Methyl-6,10-methyl bridge-1Η-imidazo[5,4_i][3]benzoazepine 135590.doc • 140· 200927115

NH

Mass Spectrum (ESI+): m/z = 242 [M+H] + EXAMPLE XXXVII

(2 and, 65)-6,11,11-trimethyl-3-(2,2,2-trifluoro-ethenyl)-1,2,3,4,5,6-anthracene argon- 2,6-A bridge-benzo[dj 啐-8-sulfonate and (2Λ,65&gt;6,11,11βtridecyl-3-(2,2,2-trifluoro-ethylidene) -1,2,3,4,5,6-hexanitro-2,6-jiadong_stupid [d]qiqi-9-itexiong slowly added gas sulfonic acid (1.5 mL) at room temperature To 2,2,2-three gas [(2/?,6&lt;S)-6,ll,ll-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge- Stupid and [d] azin-3-yl]-ethanone (0·90 g) in a solution of di-methane (10 mL). Next, the solution was stirred overnight at ambient temperature. The solution was poured into ice-cold water. The resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO4). Purification

Yield: 1.18 g Example XXXVIII 135590.doc

200927115 (2/^65)-6,11,11 trimethyl-1,2,3,4,5,6·hexa-argon-2,6-methyl bridge-benzo[d] gas 唓-8-sulfonate Dimethyl hydrazide and (2圮645)_61111_trimethyl-1'2,3'4,5,6-hexa-argon-2,6-methyl bridge-benzo[d] gas + -9-continued Dimethylamine is added to dimethylamine (3.3 mL '2 in THF) to hydrazine in ethanol (5 mL) and cooled in an ice bath _ trimethyl _3_(22,2-difluoro- Ethyl)-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[[1]azepine-8_sulfonate and (2/?,65)_6 ,11,11-trimethyl_3-(2,2,2-trifluoro-ethenyl)_, 2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo [d] A mixture of azepine-9-sulfonate (〇.9〇g, 〇 from the crude product of Example XXXVII). Remove the cooling bath and mix the solution for 2 h at ambient temperature. Then add 4 M NaOH. Solution (2.2 mL) to cleave the difluoroacetic acid group. After stirring for 1 h at room temperature, the solution was diluted with water and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgS 〇4). The solvent was removed and the residue was purified with EtOAc EtOAc (EtOAc) ,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge_benzo[1] W nitrogen 4-8-sulfonic acid dimethylamine: Yield: 50 〇 11^ (710/〇 of theory) Mass (ESI+): m/z = 323 [M+H] + (2 &, 6S&gt;6,11,11-trimethyl-1,2 ,3,4,5,6-hexahydro-2,6-methyl bridge·benzo[d]azin-9-sulfonic acid dimethylamine: yield: 50 mg (7% of theory) mass spectrum ( ESI+) ·· m/z=323 [M+H] + The following compounds were obtained in analogy to Example XXXVIII: 135590.doc -142· 200927115 (1) (2Λ,6*5)-6,11,11-Third 1,2-, 2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine-8-sulfonic acid formamide

Ο Mass Spectrum (ESI+): m/z = 309 [M+H] + Methylamine was used as a coupling partner. (2) (2/?,6S)-6,ll,ll-trimethyl-1,2,3,4,5,6-hexahydro-2,6-anthracene-benzoindole[d]nitrogen啐-8·sulfonamide

Mass Spectrum (ESI+): m/z = 295 [M+H] +.

Example XXXIX

1-[(2 and 65&gt;8-ethenyl-6,11,11-trimethyl_12S6 tetraargon 4H 2 6 alpha bridge-benzo[d]nitrozol-3-yl]_2,2, 2-trifluoroethyl ketone and 1_[(2 and 65)_9 acetyl -6,11,11-trimethyl-1,2,5,6-tetra-argon-411-2,6-methyl bridge- Benzopyrene (1)azin-3-yl b 2,2,2-trifluoro-ethylamine Ethyl chloride (0.25 mL) was added to an ice bath to cool AlChCl.3 g) in dichloromethane (5 In the suspension in mL). After stirring the mixture for 5 min, add (2/^65)-2,2,2-three gas dissolved in di-methane (5 mL) by 135590.doc •143· 200927115 Small (6,11,11-tridecyltetrahydro-4H_2,6-methyl bridge_benzo[d]azepine-based)-ethylidene (1.0 g). The mixture was stirred overnight at ambient temperature and then poured. Into ice-cold, semi-concentrated hydrochloric acid (20 mL), EtOAc (EtOAc) The residue was purified by EtOAc (EtOAc/EtOAc (EtOAc:EtOAc): Quality Spectrum (ESI+) : m/z=354 [M+H] +

Instance XL

1-[(2/?,65&gt;6,11,11-trimethyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge_benzo[d]azepine- 8-yl]-ethanone and 1-[(2J?,65)-6,11,11-trifyl-1,2,3,4,5,6-hexa-2,6-methyl bridge- Benzopyrene 6]methane-9-yl]-Bing Ming 4 M NaOH solution (2.5 mL) was added to l-[(2i?,6S)-8-ethylindolyl] 6,11,11-triterpene Base-1,2,5,6·tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen-3-yl]-2,2,2-trifluoro-ethanone with 1-[( 2 and, 615)-9-ethenyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-anthracene-benzo[d]azepine- 3-Alkyl-2,2,2-trifluoro-ethanone (0.83 g) in a mixture of about 3:1 in decyl alcohol (10 mL). The resulting solution was stirred overnight at room temperature. The residue was purified by reverse phase HPLC (acetonitrile / water / NH3) to give the title compound 135 590. doc. 144 - 200927115. Yield: 0.35 g 1-[(2) /?,65)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-anthracene-benzo[nitrogen 4-8-yl]- Ethyl ketone and 0.0781-[(2 free 6 magic-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[[1] Nitrogen 4-9-yl]-ethanone (combination is the theoretical value 7 1%) Mass Spectrum (ESI+): m/z = 258 [M+H] + The following compounds are obtained in the same manner as in Example XL: (1) (2/?, 6 and, &gt;8-hydroxy-6,11- Dimethyl-1,2,3,4,5,6-hexahydro-© 2,6-methyl bridge-benzo[d]nitrogen-9-indolecarbonitrile

Mass Spectrum (ESI+): m/z = 243 [M+H] + (2) (2i?,6*S)-8-decanesulfonyl-6,11,11-trimethyl-1,2, 3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine

Mass Spectrum (ESI+): m/z = 294 [M+H] + (3) (2/?,65&gt;10-methanesulfonyl-6,11,11-trimethyl-1,2,3,4 ,5,6-hexahydro-2,6-methyl bridge-benzo[d]nitrogen_

135590.doc -145- 200927115 Mass Spectrum (ESI+): m/z=294 [M+H] + (4) (6π,101S^)-5,6,7,8,9,10-hexahydro-2, 10,12,12-tetramethyl-6,10-methyl bridge-lH-imidazo[5,4-i][3]benzone nitrogen 4

(5) (6/?,105&gt;5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methyl bridge-1H-imidazo[5,4 -i][3]benzone nitrogen 4

(6)(2/?,6/?,11 magic-6,11_dimethyl-7-nitro-1,2,3,4,5,6-hexahydro-2,6-methyl bridge- Benzo[d]nitro-8-ol

Mass Spectrum (ESI+): m/z = 227 [M+H] + (7) (6/?, 105&gt;5,6,7,8,9,10-hexahydro-10,12,12-trimethyl -6,10-A bridge-1H-triazolo[5,4-i][3]benzone nitrogen 4

Mass Spectrum (ESI+): m/z = 257 [M+H] + (8) (67?, 105&gt;5,6,7,8,9,10-hexahydro-10,12,12-trimethyl- 2-pyrazin-2-yl-6,10-methyl bridge-111-imidazo[5,4-1][3]benzoazepine 135590.doc -146- 200927115

Mass Spectrometry (ESI+): m/z = 334 [M+H] + (9) (6^105)-2-(1-ethyiyl-piperidin-4-yl)-5,6,7,8, 9,10-hexahydro-10,12,12-tridecyl-6,10-methyl bridge-111-imidazo[5,4-anthracene][3]benzone nitrogen 4

❹ (10) (6i?,10&lt;S)-2-cyclopropyl-5,6,7,8,9,10-hexahydro-1〇,12,12-trimethyl-6,10-曱Bridge-111-imidazo[5,4-丨][3]benzoazepine

(12) (6i?, 105)-2 - tert-butyl _5,6,7,8,9,10-hexahydro-1 fluorene, 12,12-trimethyl-6,10-methyl bridge- 1H-imidazo[5,4-i][3]benzoazepine

(13) (6/?,10&lt;5)-5,6,7,8,9,10,hexahydro_10,12,12-tridecyl_2_〇bite-3-yl-6, 10-曱 bridge-11*1-'1m1 sit and [5,4-1][3]benzoazepine

135590.doc -147- 1 (6/?,1〇15)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(1-methyl- 6-Sideoxy-1,6-dihydro-&quot;Bitter-3-yl)-6,1 〇-A bridge-1H-midindole[5,4-i][3]benzone4 200927115

(14) (6i?,10*S)-5,6,7,8,9,10-hexahydro-i〇,i2,i2-trimethyl-2-IXS) tetrahydrocarbamate-2-yl ]-6,10-甲桥-1H-°米唾和[5,4_丨][3]Benzene gas

Mass Spectrum (ESI+): m/z = 326 [M+H] + ❹ (15) (6 free 10 &lt; 5) -5,6,7,8,9,10-hexahydro-i〇,i2,12- Trimethyl-2-methylazin-4-yl-6,10-methyl bridge-1H-imidazo[5,4-i][3]benzoazepine

(16) (6/?,105&gt;5,6,7,8,9,10-hexahydro-i〇,i2,12-trimethyl-2-(5-methylpyrazin-2-yl) -6,10-曱桥-1H-imidazo[5,4-i][3]benzoazepine

Mass Spectrum (ESI+): m/z = 348 [M+H] + (17) (6/?, 105&gt;5,6,7,8,9,10-hexahydro-1〇,12,12-triter Benzyl-2-[(and)-tetrahydrofuran-2-yl]-6,10-methyl bridge-1H-imidazo[5,4-i][3]benzonitrile 4

Mass Spectrum (ESI+): m/z = 326 [M+H]+ (18) (7/?,11/?,125&gt;6,7,8,9,10,11-hexahydro·2,11,12 -trimethyl 135590.doc •148· 200927115 6,10-曱 bridge-oxazole[4,5-h][3]benzone nitrogen 4

Mass Spectrum (ESI+): m/z = 257 [M+H] + (19) (6 &, 10$)-5,6,7,8,9,10-hexahydro-2,1〇,12,12 -Tetramethyl_6 1〇甲桥-oxazolo[4,5-i][3]benzoazepine

(20) (6/U〇5&gt;2-cyclopropyl-5,6,7,8,9,1〇-hexa-argon_10,1212_trimethyl-6,10-methyl bridge-oxazole [4,5- to 3]benzoazepine

(21) (6/?,10/?,125&gt;5,6,7,8,9,10-hexahydro-2,1〇,12-trimethyl 6,10-methyl bridge-oxazole[ 5,44][3]benzoazepine

Mass Spectrum (ESI+): m/z = 257 [M+H] + (22) (67?,10/?,125)-2·cyclopropyl-5,6,7,8,9,l〇-six Hydrogen_1〇12 methyl-6,10-methyl bridge-oxazolo[5,4-i][3]benzone nitrogen 4

135590.doc -149· 200927115 (23) (67U0 phantom-2-tert-butyl-mm, hexahydro-indole 1212 trimethyl-6,10-methyl bridge-oxazole[4,5- to 3 Benzodiazepine 4

(24) (6/?,105&gt;5,6,7,8,9,1〇-hexahydro-1〇,12,12-tridecyl_2-(5-methyl-0 than 嗓-2 -yl)-6,10-A bridge-oxo and [4,5-i][3]benzoazepine

Instance XLI

1_[(21?,6/?,115&gt;9-bromo-8-hydroxy-6,11.dimethyl-indole, 2,5,6·tetrahydro-4H-2,6-methyl bridge-benzo丨d]azin-3-yl]·2,2,2-trifluoro-ethanone Stir 2,2,2-trifluoro-1-[(2/?,6/?,115&gt) at 80 °〇 ;8-hydroxy-6,11-dioximemethyl-^btetrahydro-^^...-methyl bridge-benzo(4)azinium-yl-bethyl ketone (3.0 g) and tribromide pyridinium (3.3 g The solution in acetic acid (2 mL) was stirred for 2 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, aqueous NaHC03 and brine. After the solvent was removed and the residue was purified by EtOAc (EtOAc/EtOAc:EtOAc:EtOAc: z=392/394 (Br) [M+H] + 135590.doc -150- 200927115 The following compounds were obtained analogously to the example XLI: (1) 1-[(2/?,6/2,11_/?)- 9-Bromo-8-carbyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]aza-4-3yl]-2 2,2-trifluoro-ethanone

Br,

HO Mass Spectrometry (ESI+) : m/z = 392/394 (Br) [M+H] +

Example XLII

Ο (2/?,6Ι?,1ΐα-8-hydroxy-6,11-dimethyl-3-(2,2,2-trifluoro-ethenyl)-1,2,3,4,5, 6-hexahydro-2,6-methyl bridge-benzo[d] gas-9- formazan 1-[(2 and 6,6 and,11*5)-9-bromo-8-pyridyl-6 ,11-Dimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]-2,2,2-trifluoro-B A mixture of the ketone (〇.50 g) and copper cyanide (0.23 g) in N-methyl-pyrrolidone (2 mL) was stirred in a microwave oven for 1 h at 180 ° C. After cooling to room temperature, Water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (Na.sub.2.sub.4). After solvent was removed, to eluent chromatography (cyclohexane / ethyl acetate 2:1 - 1:2) Purification of residue. Yield: 0.20 g (46% of theory). Mass. (ESI+): m/z = 339 [M+H] + The following compounds are similar to the example XLII: (1) (2 /?,6Λ,11/?)-8-Hydroxy-6,11.dimethyl-3-(2,2,2-trifluoroethyl)-1,2,3,4,5,6 - hexahydro-2,6-fluorene bridge_benzo[[1]azepine_9_carbonitrile 135590.doc • 151 . 200927115

Mass Spectrum (ESI+): m/z = 339 [M+H] + EXAMPLE XLIII

(2 and, 6i?, llS)-6,ll-dimethyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzo[d]azepine-9- Formaldehyde to (2 first 6/?,115)-trifluoro-methanesulfonic acid 9-cyano-6,11-dimethyl-3-(2,2,2-trifluoro-ethenyl)-1 , 2,3,4,5,6-hexahydro-2,6-anthracenyl-benzo[d]azul-8-yl ester (0.30 g) and Pd(OAc)2 (7 mg) in tetrahydrogen A solution of KF (76 mg) in water (100 mL) was added to a mixture of EtOAc (3 mL), followed by polymethylhydroquinone (1.0 g). The resulting mixture was stirred at room temperature overnight, then 1 M NaOH (20 mL) was added. After vigorous stirring for 1 h, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried (MgSO4). The solvent was removed and the residue was taken in EtOAc EtOAc (EtOAc) Next, the solution was neutralized with 1 Μ hydrochloric acid, filtered, concentrated, and then purified and purified. Yield: 0.07 g (48°/〇 of theory) Mass Spectrum (ESI+): m/z = 227 [M+H] + The following compound was obtained similar to Example XLIII: 135590.doc -152- 200927115 (1) ( 2i^6Λ,ll/?)-6,ll-dimethyl-1,2,3,4,5,6-hexahydro-2,6,methicone_benzo[d]nitrogen4·9-A Nitrile

Bromo-MM1-trimethyl-1,2,5,6-tetrahydro, 4H-2,6-methyl bridge_benzoxanthene&lt;1]azepin-3-yl]-2,2,2-tri Fluorine-hexanone and 1_[(2 and 645)-10_1 bromo-6, ιι, ιι-trimethyltetrahydro _4H_26 alpha bridge benzo[d] 氚啐 3 1-2, 2, 2-three Fluorine-ethyl hydrazine adds 八1(:13(147 11^) to 2,2,2-trifluoro-1-[(2 and,6&lt;5)-6,1111_ = thiol-1,2,5 ,6-tetrahydro-411-2,6-methyl bridge_benzo[(1]azol-3-yl]-ethanone (275 mg) in 1,2_dioxaethane (1 mL) In the solution, the resulting mixture was stirred at ambient temperature for 10 min, followed by the addition of bromine (52 μ! 〇. The mixture was heated to 50 VII. After stirring at 50 ° C for 1 h, the mixture was cooled to ambient temperature and The mixture was diluted with water (30 mL) and water (10 mL), and the mixture was vigorously mixed for 5 min and then 4 Μ hydrochloric acid was added (10) The organic phase was separated and washed with 4 HCl hydrochloric acid and water and dried (MgS 〇 4). The solvent was removed under reduced pressure to give the title compound as a mixture of sssssssssssssssssssssssssssssssssssssssssssssssss

Mass Spectrum (ESI+): m/z = 390/392 (Br) [M+H] + EXAMPLE XLV

2.2.2- Difluoro-1-[(2/?,6*5)-8-甲烧烧雄基-6, ιι,ιι_ trimethyl _ 1,2,5,6-tetra argon_411-2 , 6_甲桥-Benzo[&lt;1]azin-3-yl]-ethanone and 2,2,2-

Trifluoro-1-[(2Λ,6·5)·10-methanesulfonyl-6,n,u_trimethyl_1 2 5 6 tetra- 4H-2,6-methyl bridge-benzo[ d] gas-3-yl--ethyl-addition of MeSO2Na (0.79 g) to Cul (1.5 g) and 14 (2/^65)-8^-6,11,11-trimethyl_1,2 ,5,6-tetrahydro-411-2,6-methyl bridge_benzo[[1]azepine-3-yl]-2,2,2-trifluoro-ethanone/i_[(2/?, 65&gt; 10-Bromo-6,11,11-tridecyl_ 1,2,5,6-tetrahydro-411-2,6-anthracenyl-benzo[[1]aza 4-3-yl]- 2,2,2-Trifluoro-ethanone (300 mg of the crude product from Example XLIV) in a mixture of dimethyl sulfoxide (6 mL). The mixture was heated to 12 ° C and at this temperature After stirring overnight, the mixture was poured into a concentrated aqueous ammonia solution (20 mL) and water (80 mL). The mixture was extracted with ethyl acetate and washed with brine and brine. After drying (MgS 〇 4), the solvent was removed under reduced pressure and the residue was purified to purified crystall [(2i?,6jS)-8-甲烧烧基-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d ] 4-3-yl]-ethanone: Yield: 150 mg (50% of theory) Mass Spectrum (ESI+): m/z=390 [M+H] + 135590.doc •154- 200927115 2,2,2 -trifluoro-1-[(2Λ,65&gt;10-decanesulfonyl-6JM1·trimethyl_ 1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d] Nitroindol-3-yl]-acetamidine: Yield: 100 mg (33% of theory) Mass (ESI+): m/z = 390 [M+H] +

Instance XLVI

2,2,2-trifluoro 11,11-trimethyl-8,9-di-decyltetrafluoro-4H-2,6-methyl bridge-benzo[d]azepine-4-ol]-ethanone Nitric acid (0.16 mL) was added to a solution of trifluoroacetic acid (0.65 mL) in EtOAc (4 mL). After stirring for 1 〇 min, add 2,2,2·trifluoro+[(2 and 6,6 outside 6,11,11-trimethyl_1,2,5,6- in dichloromethane (5 mL)) Tetrahydro-4Η·2,6-methyl bridge-benzo[d]azepine-3-yl]-ethanone (0.50 g). The resulting solution was stirred in a cooling bath for 2 h and then stirred overnight at ambient temperature. The solution was poured into ice-cold water and the resulting mixture was extracted with a dioxon. The combined organic benzene &amp; sputum was washed with aqueous NaHCO 3 and dried (MgSCU). Silicone

Chromatography (cyclohexane / ethyl acetate 1:0 - 9:1): EtOAc: EtOAc: EtOAc: 135590.doc -155- 200927115

^[(2/^65)-8,9-Diamino-6,11,11-trimethyl-1,2,5,6-tetrahydrogen, 4H_ 2,6_methyl bridge-benzo[d啐N-啐_3_基】_2,2 2_Trifluoro-ethanone oscillates 10% palladium/carbon (300 mg) and (2Λ,65)-2,2,2-three under hydrogen atmosphere at room temperature Fluor-1-(6,11,11-trimethyl-8,9-dinitro-1,2,5,6-tetrahydro-4Η- 2,6-methyl bridge-benzo[d]azepine A mixture of -3-yl)-ethanone (330 mg) in decyl alcohol (5 mL) for 2 h. Next, the catalyst was isolated by filtration and the solvent was evaporated to dryness crystals. Yield: 260 mg (93% of theory) Mass Spectrum (ESI+): m/z = 342 [M+H] + The following compounds are obtained in the same manner as Example XLVII: (1) 1-[(2圪67?,11&lt;;5)-7-Amino-8-hydroxy-6,11-dimethyl 1256 tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]-2,2, 2-trifluoro-ethanone

Mass Spectrum (ESI+): m/z = 329 [M+H] + (2) l-[(2/?,65&gt;8-amino-9-hydroxy-6,11,11-trimethyl]2 5 6 tetrahydro-4H-2,6-anthracene-benzo[d]azepine_3_yl]-2,2,2-three gas_element

135590.doc •156- 200927115 Mass Spectrum (ESI+): m/z=343 [M+H] + (3) 14(2/^6/^115)-9-Amino-8-hydroxy-6,11- Dimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azac-3-yl]-2,2,2-trifluoro-ethanone

Mass Spectrum (ESI+): m/z = 329 [M+H] + EXAMPLE XLVIII

(7/?,115)-6,7,8,9,10,11-hexahydro-11,13,13-trimethyl-7,11-methyl bridge-pyrazine[2,3"][ 3] Benzodiazepine Glyoxal (40% in water, 95 μ! 〇 was added to dissolve in ethanol (3 mL) and cooled in an ice bath (2/?,65&gt;l-(8,9 -diamino-6,U,ii-trimethyl·1,2,5,6-tetrahydro-4Η-2,6·methyl bridge-benzo[d]azepin-3-yl)·2, 2,2·trifluoro-ethanone (260 mg). The cooling bath was removed and the solution was stirred overnight at ambient temperature. The solution was then concentrated and the residue dissolved in methanol ( 丨mL) and 4 M aqueous NaOH ( Treatment with 0.38 mL). After stirring overnight at ambient temperature, then brine was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSCU) and solvent was removed under reduced pressure. The title compound was used without further purification. Yield: 204 mg Mass Spectrum (ESI+): m/z = 268 [M+H] + 135590.doc • 157 · 200927115 The following compounds were obtained similarly to Example XLVIII : (1) (7^115)-6,7,8,9,10,11-hexahydro-2,3,11,13,13-pentamethyl·7,11-曱 bridge-pyrazine And [2,3-i][3]benzone nitrogen 4

Mass Spectrum (ESI+): m/z = 296 [M+H] + This compound was obtained by using ethyl hydrazide according to the procedure described above. (2) (7i^,115&gt;6,7,8,9,10,ll-hexahydro-3,ll,13,13-tetramethyl-7,l-b-bridge-o-pyrazine[2, 3-i][3]benzodiazepine and (7/^,ll4S&gt;6,7,8,9,10,n-hexahydro-2,11'13,13-tetramethyl-7,11- A bridge-pyrazine-[2,3_i][3]benzone nitrogen 4

Mass Spectrum (ESI+): rn/z = 296 [M+H] + The compounds were obtained as a mixture of each other by using methylglyoxal.

© Example IL 2,2,2-Trifluoro-

- two mice-1-[(6 and, 1(^)-5,6,7,8,9,1〇-hexahydro-yl-M G_甲桥·1Ηκ丨Μ]]丨y benzo Nitrogen was dissolved in glacial acetic acid at a temperature of 130 C. 6,11,11-trimethylammonium 9 A m. Dimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge_2, 1〇,12,12-tetramethylxin·7·yl]-B_(2/?,65&gt;1_(8,9-diamino:,6-A bridge, stupid [d]-azapine _3 135590.doc •158· 200927115 base)-2,2,2-trifluoro-ethanone (600 mg) for 3 h. After cooling to ambient temperature, the solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic solution was washed with EtOAc (aq. EtOAc) (EtOAc) m/z = 366 [M+H] + The following compounds are obtained analogous to the example IL: (1) 2,2,2-trifluoro-1-[(6Λ,105&gt;5,6,7,8,9, 10-hexahydro-10,12,12-© trimethyl-6,10-methyl bridge-1H-imidazo[5,4-i][3]benzoazepine-7-7-yl]-ethanone

The reaction is carried out using formic acid instead of acetic acid. Instance L

(6 and, 1045)-5,6,7,8,9,10-hexa-argon-3,10,12,12-tetramethyl-6,10-methyl bridge-imidazo[4,5-i]丨3]benzodiazepine and (6/?,10&lt;S)_5,6,7,8,9,10-hexa-argon-1,10,12,12·tetradecyl-6,10-meth bridge -Imidazo[5,4-i]丨3]benzodiazepine iodonane (69 μ!〇 added to 2,2,2-trifluoro-1-[(6 and, 105&gt; 5,6, 7,8,9,10-hexahydro-10,12,12-tridecyl-6,10-methyl bridge-1Η-imidazo[5,4-1][3]benzoazepine-7-yl ]-Ethyl ketone (300 11^) and ": 2 (: 〇 3 (118 111§) in B5590.doc • 159 · 200927115 ^ mixture of methyl decylamine (2 mL) The resulting mixture was stirred overnight. Then, water was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO.sub.4). The solvent was removed and the residue was dissolved in methanol (3 mL) And treated with 4 mn aqueous solution (7) 5 _. The solution was diluted at room temperature (iv) overnight and then diluted with ethyl acetate. The saponin was washed with water and brine and dried (MgS 〇 4p was removed under reduced pressure) The crude title compound is obtained as a mixture. Yield: 90 mg (39% of theory) Example L was based similarly obtained: ⑴ (6 / ?, l〇 &lt; S) -5,6,7,8,9, l〇- hexahydro ^, _ group 2,10,12,12- five Yue

Mo-曱 bridge-imidazo[5 4_i][3]benzoazepine

Mass Spectrum (ESI+): m/z = 284 [M+H] + (2) (6/?,1〇5&gt;5,6,7,8,9,1〇-hexahydro-2,3,1〇 ,12,12-pentamethylene _ 〇6'10-methyl bridge-imidazo[4,5-丨][3]benzoazepine

Qualification (ESI+): m/z = 284 [M+H] + The two isomeric compounds (1) and (2) were obtained from the same starting compound and separated by reverse phase HPLC. (3) (6^105)-5,6,7,8,9,1〇-hexahydro_11〇,12,12_tetradecyl_61〇_ bridge-triazolo[5,4- i][3]benzodiazepine with (67?,1〇(5)_5,6,7,8,91〇_six 135590.doc -160- 200927115 hydrogen-3,10,12,12-four a mixture of _6,1〇-methyl bridge-triazolo[4,5-anthracene][3]benzone nitrogen 4

These compounds were obtained from the compound example LIX after carrying out the reaction as described above.

Instance LI

2-Benzyl·2_aza·bicyclo[3.3.1]壬-6·Alcohol Add diisobutylaluminum hydride (1.5 mol/L in toluene, 21 mL) to cool to -70 °C 2-Benzyl-3-oxo-2-azino-bicycloacetate [3.3.^壬·6 based on hydrazine (1.50 g, see c/ze/w. iS&quot;oc_, 7 1999' 11 57 for synthesis) -11 62) In a solution of toluene (30 mL). Remove the cooling 0 bath and mix the solution overnight at ambient temperature. Then another portion of hydrogenated isobutylaluminum (1.5 mol/L in toluene, 20 mL) was added and the mixture was stirred at room temperature for 4 h. Next, the solution was poured into ice-cold water and the resulting mixture was extracted with ethyl acetate. The aqueous phase was acidified with 4 mL of HCl and then extracted with ethyl acetate. The combined organic extracts were dried (Na.sub.2) and solvent was removed. The residue was purified by silica gel chromatography (dichlorohexane / methanol: hexanes). Yield: 440 mg (36% of theory) 135590.doc -161 - 200927115 s. /z=232 [m+H] +

Example LII

2_Benzyl-2-aza-bicyclo[3 3...壬"·ketone was added to Dess-Martin periodinane (1.3〇g) to 2-cell base-2 cooled in an ice bath - aza-bicyclo[3.3.1]-non-6-ol (0.60 g) in a solution of dichlorohydrazine (丨 5 mL). The cooling bath was removed and the solution was stirred at ambient temperature for 1 h. 'The solution was diluted with di-methane and washed with a mixture of aqueous Na 2 S 2 3 solution and aqueous NaHCO 3 solution. The solution was dried (NazSO 4) and the solvent was removed. by gel chromatography (dioxane / decyl alcohol 1:0-2: 1) Purification of residue. Yield: 25 0 mg (42% of theory). MS (ESI+): m/z=230 [M+H]+

Example LIII

❹ 3 - nodal base 2,3,4,5,6,7-hexanitro-2,6-a bridge-111-gas 吟[5,4-1)]&quot;5 丨味2- 2- Add a solution of the base-2-aza-bicyclo[3.3.1]壬-6-net in acetic acid (〇·24 g) to PhNHNH2*HCl (173 mg) in acetic acid (4 mL) heated at reflux temperature. In the solution. After stirring at this temperature for 2 h, the solution was cooled to room temperature and a K 2 C 3 aqueous solution was added. The resulting mixture was extracted with ethyl acetate, and the combined organic extracts were dried (Na.sub.2) and solvent was removed. The residue was purified by reverse phase HPLC (MeCN / water) 135590.doc -162. Yield: 160 mg (49% of theory)

Instance LIV

2-benzyl-1,4,6-trimethyl-1,2-diar-pyridine

PhCH2MgCl (1 Torr in Et20, 180 mL) was added dropwise to a solution of iodized 1,2,4-trimethyl-pyridinium (24.3 g) in Et2O (90 mL) cooled in an ice bath. . After stirring for 2 h in an ice bath, the solution was poured into a mixture of 72% aqueous HCl solution (40 mL) and crushed ice (about 900 mL). The resulting mixture was stirred for 1 h and the precipitate formed was separated by filtration. The precipitate was washed with decyl alcohol and dried to give the title compound. Yield: 22.6 g (74% of theory) Mass (ESI+): m/z = 214 [M+H] +

Instance LV

6-Benzyl-1,2,4-trimethyl-1,2,3,6-tetra-argon-pyridine and 2-benzyl·1,4,6·trimethyl-1,2,3,6 - Tetra-nitrogen bite NaBH4 (3.8 g) was added in portions to 2-benzyl-1,4,6-trimethyl-1,2-dihydro-pyridine (22.6 g) in MeOH (65 mL) And in a solution of NaOH (1 Μ in water, 200 mL). The resulting mixture was scrambled at room temperature for 20 min and stirred at 60 ° C for 30 min at 135590.doc -163 - 200927115. After cooling to ambient temperature, the mixture was diluted with water (150 mL) and extracted with Et.sub.2 (3×l 50 mL). The combined organic extracts were dried <RTI ID=0.0> Yield: 11.7 g (76% of theory) Mass (ESI+): m/z = 216 [M+H] +

Instance LVI

〇3.4.6- Trimethyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzo[[1]nitrogen 4 will be 6-benzyl-1,2,4 a mixture of tridecyl-1,2,3,6-tetrahydro-acridine with 2-benzyl-1.4.6-trimethyl-l,2,3,6-tetrahydropyridine (from example lv, 11.7 g) in combination with 48% HBr in water (30 mL) and 33% HBr in acetic acid (20 mL). The mixture was heated to reflux temperature and mixed for 4 d at this temperature. After cooling to ambient temperature, be careful Ammonia (32%, 45 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were extracted with 2 EtOAc (3×50 mL) and basified with 32% aqueous ammonia (20 mL) The combined aqueous extracts were extracted with aq. EtOAc (MeOH) (EtOAc) 5-75:25:2.5) Purification of the title compound was obtained eluted from EtOAc EtOAc EtOAc EtOAc 15% of the theoretical value) 135590.doc -164- 200927115

Mass Spectrum (ESI+): m/z = 216 [M+H] + EXAMPLE LVII

4,6-Dimethyl-1,2,5,6-tetraar-4H-2,6-methyl-benzo[d]azane_3_carbonitrile (a diastereomeric hydrazine, above The relative configuration of the substituents given in the plotted structures is confirmed by NMR) 3,4,6-trimethyl-i, 2, 3, 4, 5 dissolved in CH2C12 (40 mL) ,6-Hexahydro-2,6-methyl bridge-benzo[d]azepine (from example LVI, 1.7 g) was added to BrCN (1.77 g) cooled in an ice bath in CH2Cl2 (10 mL) In the solution. The cooling bath was removed and the mixture was stirred at ambient temperature for 1 h and at 45 °C for 2 h. After cooling to ambient temperature, the solution was washed with water, 2 Μ hydrochloric acid, and 1 〇% K^CO; The solution was dried (MgS 〇 4), the solvent was removed, and the residue was triturated with a small portion of acetone to give the title compound. Yield: 0.98 g (54% of theory). Mass. (ESI+): m/z = 227 [M+H] + The following compound was obtained in the same manner as in Example LVII: (1) 5,6-didecyl-l, 2,5,6-tetrahydro·4Η-2,6-fluorene bridge-stupid [d]azaindole-3-pyridonitrile (racemic mixture of diastereomers shown)

Mass Spectrum (ESI+): m/z = 227 [M+H] + starting compound 3,5,6-trimethyl·ι,2,3,4,5,6-hexahydro-2,6-methyl bridge - stupid and 135590.doc • 165- 200927115

[(1) Azide can be obtained as described in 1/.^^. (:/^. 1971, 14, 5 65-68. Example LVIII

3,4,6-trimethyl-l,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzoindole d]nitrogen 4 (except the diastereomers shown) Racemic mixture) 4,6-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4 -3-^carbonitrile (a non-pair A mixture of chloroform (925 mg), water (30 mL) and EtOAc (30 mL) After cooling to ambient temperature, the solution was basified with a concentrated aqueous ammonia solution and the mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine and dried (MgSO. The solvent was removed under reduced pressure to give the title compound. Yield: 439 mg (53% of theory) Mass (ESI+): m/z=202 [M+H] + The following compound was obtained in the same manner as in Example LVIII: Q (1) 5,6-dimethyl-1 , 2,3,4,5,6-hexahydro-2,6-methyl bridge_stup [[1]azepine (racemic mixture of diastereomers shown) Mass Spectrum (ESI+): m /z=202 [M+H] +

Example LIX 135590.doc -166 - 200927115

2,2,2-trifluoro-l-[(6 and,105)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl·6,10-methyl bridge -1H-Triazolo[5,4-i][3]Benzazepine 4-7-yl]-acetamidine A solution of NaN〇2 (330 mg) in water (2 mL) was slowly added to the solution. Stir bar, 1-[(2Λ,65&gt;8,9-diamino-6,11,11·trisyl-i, 2,56-tetrahydro-4H-2,6-methyl bridge-benzo[ d] Nitrogen 4-3-yl]_2,2,2-trifluoro-ethylidene (65 〇mg) and acetic acid (15 mL) and the flask was cooled in an ice bath. The obtained mixed mash was placed in a cooling bath. Stirring for 2 h and stirring at ambient temperature for 1 h. The title compound was obtained without further purification. · 610 mg (91% of theory) Mass Spectrum (ESI+): m/z=353 [M+H] +

Instance LX

(2^,6Λ,.pentan-2-yl)-1,2,5,6 tert-butyl • dimethyl-8-(4,4,S,5-tetramethyl·[Μ,2 Dioxonium 6-tetrahydro-4Η-2,6-anthracenyl-benzo[d]azepine-3carboxylic acid will be equipped with a stir bar, decyloxy-1,2,5,6-, dibutyl Ester (9.90 g), i, (5), 6/?, 11 phantom-6,11-dimethyltrifluoromethanesulfonate. Tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine·3 • Formic acid double (pinacoldin) diboron (6.15 g), l5l, _ double (two 135590.doc -167- 200927115 phenylphosphino) ferrocene (0.73 g) and H (5G) flask Rinse with stars for 15 min. Next, add bis-bis(diphenylphosphino)-ferrocene-dipalladium dichloromethane complex (1.08 g) and heat the mixture to 8 (rc. at 8 After 扰&lt;&gt;c under stirring for 2 d and cooling to ambient temperature, the mixture was diluted with 〇Me (i5 〇 mL) and washed with water (3 x 100 mL) and brine (1 χ 1 〇〇 mL). The title compound was obtained as a colorless oil. EtOAc: m. 6.90 g (73% of theory) Mass Spectrometry (ESI+) : m/z=428 [M+H] +

Example LXI

Ο (2 and, 6/?, 115)-6,11-dimethyl·8_boron-1,2,5,6-tetra-argon·4Η-2,6-methyl bridge·benzo[d]azepine 3-butylic acid tert-butyl ester was stirred at room temperature (2/?,6圪11 幻-6,11-dimethyl-8-(4,4,5,5-tetradecyl-[1,3 , 2] diboronol-2-yl)-1,2,5,6-tetrahydro-411-2,6-methyl bridge-benzo[d]nitrogen 4-3-carboxylic acid tert-butyl ester ( 2.50 g) and a solution of NaI04 (5.00 g) in 1N aqueous solution of NH4OAc (34 mL) and acetone (60 mL) overnight, then water was added to the residue and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with EtOAc EtOAc (EtOAc m. 91% of the value)

Mass Spectrometry (ESI·) ·· m/z=390 [M+HCOO]· Example LXII

(2/?,6/?,ll»S)-6,ll-dimethyl-8-(2-methyl- shouting-4-yl)-i,2,3 4 5 6 in six argon- 2,6-A bridge-benzoxan] gas enthalpy Pd(OAc)2 (3.3 mg) was added to (2/?,6/?,115)-6,11_ dimethyl- under argon atmosphere 8-boro-1,2,5,6-tetrahydro-411-2,6-anthracene-benzo[[1]azepine_3_曱酉夂second butyl S曰(0.30 g), 4· Gas-2-methyl-mouth (93 mg), K3PO4 (0.31 g) and 2-dicyclohexylphosphino-2,6,-dimethoxybiphenyl (11 5 mg) in n-butanol The mixture was heated to 100 ° C and stirred at this temperature overnight. After cooling to room temperature, ethyl acetate was added and the mixture was filtered and concentrated under reduced pressure. The solution was dissolved in CH.sub.2Cl.sub.2 (3 mL) and EtOAc (EtOAc) (EtOAc (EtOAc) (48% of theory) Mass Spectrum (ESI+): m/z = 294 [M+H] + The following compounds are similar to the example LXII obtained: (1) (2/2,6圪11 幻-6,11-二Methyl-8-pyrimidin-4-yl-1,2,3,4,5,6-hexahydro-2,6-anthracene-benzo[d]nitrogen 135590.doc -169- 200927115

Mass Spectrum (ESI+): m/z = 280 [M+H] + EXAMPLE LXIII

(2/?,6i?,llS)-6,ll-dimethyl-8-(6-methyl-pyridazin-3-yl)-l,2,3,4,5,6- Ο hexahydro -2,6-A bridge-benzo[d]nitrogen 4 Add 2 M Na2C03 aqueous solution (1.13 mL) to (2i?,6i?,ll*S)-6,ll-dimethyl-8-(4 ,4,5,5-tetradecyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-411-2,6-methyl bridge-benzene And [Nitrate 4-3-carboxylic acid tert-butyl ester (483 mg) and 3-chloro-6-methyl-pyridazine (218 mg) in a mixture of dimethyl decylamine (2 mL). The resulting mixture was flushed with argon and then 1,1·-bis(diphenylphosphino)ferrocene-dipalladium dichloromethane complex (73 q mg) was added. The mixture was heated to 100 ° C and stirred at this temperature overnight. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified mjjjjjjjjjjjjjjj The solution was then concentrated and the residue was purified EtOAcjjjjjj Yield: 225 mg (68% of theory) Mass (ESI+): m/z = 294 [M+H] + 135590.doc -170 - 200927115 The following compounds are obtained similarly to the example LXIII: (1) (2 &lt;6/?,115&gt;6,11-Dimethyl-8-(1-indolyl-2-yloxy-12-hydrogen-pyridin-4-yl)-1,2,3,4,5,6- Hexahydro-2,6-methyl bridge·stupid [(1] nitrogen peak

Mass Spectrometry (ESI+): m/z = 309 [M+H] + Trifluoro-methanesulfonic acid 1-methyl-2-oxo-dihydro-pyridyl-4-yl ester or 4-bromo-1-indole The base bite-2-_) is used as a coupling partner. (2) 5-[(2i?,6iUl&lt;S)-6,ll-dimethyl-12,3,4,5 6 hexahydro-2 6 fluorene bridge-benzo[d]azepine-8-yl ]-1-methyl-1H-pyridin-2-indole

(3) 6_[(2圮6圪11幻-6,11-Dimethyl_12,3,4,5 6_ hexahydro-2 6-methano bridge·•benzo[d]nitrogen-8- -2-methyl-2H_chimazine _3 ketone

6-Gas-2-methyl-2H-pyridazine oxime was used as a coupling partner. (4) (2/?,6Λ,1ΐα-6,11-dimethyl·8_(2methyl-pyrimidine_5·yl)- 135590.doc -171 . 200927115 1,2,3,4,5, 6-hexahydro-2,6-methyl bridge-benzo[d]nitrogen 4

Mass Spectrum (ESI+): m/z = 294 [M+H] +

5-Bromo-2-methyl-pyrimidine was used as the coupling partner. Example LXIV

2,2,2-trifluoro-1_[(6 and,105)-5,6,7,8,9,10-hexa-argon-10,12,12-trimethyl-2-pyrazine-2- Base-6,10-Abridge-1Η-imidazo[5,4-i][3]benzoazepine-7-yl]-ethanone Stir Pyrazine-2-decanoic acid (152 mg) at room temperature ), 2-(1Η-benzotris-l-yl)-1,1,3,3-tetramethylguanidine tetramine (397 mg) and triethylamine (0.5 mL) in dimercaptomethyl hydrazine A solution of the amine (5 mL) for 30 min, followed by the addition of ΙΟ [(2Λ,65)_8,9-diamino-6,11,11-trimethyl-ι,2,5,6-tetrahydro-4Η -2,6-A bridge-benzo[d]azet-3-yl]-2,2,2-trifluoro-ethyl (300 mg). The solution was stirred overnight at room temperature. Next, the solution was diluted with Et0Ac and washed with water and 2 M aqueous KAO 3 and dried (MgSCU). The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (5 mL). The resulting solution was heated under the ribs overnight. After the solvent was removed under reduced pressure and the title compound was evaporated, mjjjd 135590.doc -172- 200927115 Yield: 380 mg (quantitative) Mass Spectrum (ESI+): m/z = 430 [M+H] + The following compounds are obtained in analogy to the example LXIV: (1) 1-[(6/? ,10幻-2-(1-Ethyl-piperidin-4yl)-5,6,7,8,9,1〇_ Liufeng-10,12,12-trimethyl-6,10 - A bridge-1H-flavored [5,4-i][3]benzone-7-yl]-2,2,2-tris-acetonitrile

Mass Spectrum (ESI+): m/z = 477 [M+H] + (2) 1-[(6/Μ(^)-2-cyclopropyl-5,6,7,8,9,10-hexahydro _10,1212_ tridecyl-6,10-曱 bridge-1H-imidazo[5,4-i][3]benzoazepine-7-7-yl]_2,2,2_trifluoro-ethanone

❿ (3) 2,2,2-trifluoro-14(6/^105^-5,6,7,8,9,10-hexahydro-_ι〇,ΐ2,ΐ2·trimethyl-2-( 1-methyl-6-o-oxy-1,6-dihydro-π ratio bit-3-yl)_6, ι〇_甲桥-1Η-imidazo[5,4-i][3]benzo Nitroth-7-yl]-ethanone

(4) 1 -[(6Λ,105^-2-Terbutyl-5,6,7,8,9,l〇-hexahydro_ι〇,ΐ2,ΐ2 三曱基_6,10-甲Bridge-1H-imidazo[5,4-i][3] benzoazepine_7•yl] 135590.doc -173- 200927115 2,2,2-trifluoro-ethanone

F (5) 2,2,2-Trifluoro_ι_[(6^105&gt;5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-pyridine-3 -yl-6,10-fluorene bridge-111-imidazo[5,4-anthracene][3]benzoazepine-4-7-yl]-acetamidine

Dimethyl-2-[(5|)-tetrahydrofurfuryl-2-yl]-6,10-methyl bridge-11^-imi"&quot; sit and [5,4-i][3]benzo Nitrogen 4-7-yl}-ethanone oxime

(7) 2,2,2-Trifluoro-indole_[(6/Μ〇5&gt;5,6,7,8,9,10·hexahydro-10,12,12·tridecyl-2-pyridazine 4-yl-6,10-methyl bridge-lH-imidazo[5,4-i][3]benzoazepine-7-yl]-acetamidine

(8) 2,2,2_trifluoro-14(6/^105)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(5-曱-Pyrazine-2-yl)-6,10-methyl bridge-1Η-imidazo[5,4-i][3]benzoazepin-7-yl]-ethanone 135590.doc -174- 200927115 ο

(9) 2,2,2-trifluoro-1-{(6/?,105&gt;5,6,7,8,9,10·hexahydro·1(),12,12 dimercapto-2- [(and)-tetrahydrofurfuryl-2-yl]-6,10-methyl bridge-ΐ Η-imiwa[5 4 i][3]benzoazepine-7-yl}-B

Mass Spectrum (ESI+): m/z = 422 [M+H] + Instance LXV

2,2,2-trifluoro 44 (7 and, 11/?, 125&gt; 6, 7, 8, 9, 1 (), 11_hexa argon 21112

Methyl·7,11-A bridge-1H-oxazole[4,5-h][3]benzoazepine_8_gibamine is dissolved in trimethyl orthoacetate (i mL) at 100 °c 1-[(2 and,6iMlS)_7_Amino-8-hydroxy-6,11-dimethyl-1,2,5,6·tetrahydro-4H-2,6-methyl bridged benzo [d] Nitrogen 4·3-yl]-2,2,2-trifluoro-ethanone (200 mg) for 3 h. After cooling to ambient temperature, the mixture was concentrated and the residue was crystallised eluted with a little methanol and dried. Yield: 100 mg (47% of theory) Mass (ESI+): m/z=353 [M+H] + The following compound is obtained in the same manner as the example LXV: 135590.doc -175- 200927115 (1) 2,2 ,2-trifluoro-1,[(6/?,105&gt;5,6,7,8,9,10-hexahydro-2,10,12,12-tetramethyl-6,10-methyl bridge- Oxazolo[4,5-i][3]benzoazepine-7-yl]-ethanone

Mass Spectrum (ESI+): m/z = 367 [M+H] + (2) 2,2,2-trifluoro·1-[(67?,10^125&gt;5,6,7,8,9,10 - hexahydro-2,10,12-trimethyl-6,10-indole bridge oxazolo[5,4-i][3]benzazepine-7-yl]-ethanone

Mass Spectrum (ESI+): m/z = 353 [M+H] Instance LXVI

Cyclopropanecarboxylic acid [(2 and 65)-9-hydroxy-6,11,11·trimethyl-3-(2,2,2-trifluoro-ethenyl)-1,2,3,4, 5,6-hexa-argon-2,6-methyl bridge-benzo[(1]nitro 4-8-yl]-decylamine Add cyclopropylformamidine chloride (0.13 mL) to i_[(2i?,65&gt ; 8-amino-9-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-41^-2,6-anthracene-benzo[«1]氤啐· a solution of 3-yl]-2,2,2-trifluoro-ethanone (〇·5〇g) and triethylamine (0.25 mL) in dioxane (3 mL). After the solution was over night, a concentrated aqueous ammonia solution (1 mL) and methanol (2 mL) were added and the mixture was stirred for a further 2 h. 135590.doc 176· 200927115 concentrated solution and water was added to the residue. The combined organic extracts were washed with EtOAc EtOAc EtOAc. Quantitative) The following compounds were obtained analogously to the example LXVI: (1) Cyclopropanecarboxylic acid [(2Λ,6/?,115&gt;9-hydroxy-6,11-dimethyl_3_(2,2,2-trifluoro-acetyl) Base)_ι,2,3,4,5,6-six Hydrogen-2,6-methyl bridge-benzo[d]azepine 4-8-yl]-guanamine

(2) Cyclopropanecarboxylic acid [(2/?,6 and 115)-8-hydroxy-6,11-dimethyl-3-(2,2,2-trifluoro-ethenyl)-1,2 ,3,4,5,6-hexahydro-2,6-anthracenyl-benzo[(1]azepin-9-yl]-guanamine

Mass Spectrum (ESI+): m/z = 397 [M+H] + (3) Ν-[(2/?,6^-9-hydroxy-6,11,U_trimethyl_3_(2 2 2• Trifluoro-ethylidene)-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge_stuppy[(:|]azepine_8_yl]_22_dimethyl- Propylamine 135590.doc 177- 200927115

F (4) 5-indolylpyrazine_2-carboxylic acid [(2 and 6,6*S)-9-carbyl- 6, ιι, ιι_trimethyl_ 3-(2,2,2-trifluoro -Ethyl)_ι,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d] akisaki-8-yl]-bristamine

Alternatively, the compound is prepared from 5-methyl-pyrazine-2-carboxylic acid as described in Scheme A using 2-(1Η·benzotriazole·ι_基 1,1 in tetrafluoromethaneamine in dimethylformamide. , 3,3-tetramethylguanidine and ethyldiisopropylamine were obtained.

Example LXVII 0

L-[(6/?,l〇S)-2-cyclopropyl_5,6,7,8,9,10-hexa-argon-1〇,12,12-trimethyl-6,1〇_曱桥-oxazolo[4,5"][3]benzoazepine_7yl]_2 2 2trifluoro-ethanone cyclopropanecarboxylic acid [(2Λ,65&gt;9-hydroxy-6,11,11 -trimethyl-3-(2,2,2-difluoro-ethinyl)-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]nitrogen A solution of 4-8-yl]-bromoamine (0.62 g) and p-toluenesulfonate (76 mg) in diphenylbenzene (6 mL) was stirred at reflux for 5 h. Solvent 135590.doc • 178· 200927115 Liquid 'Addition of ethyl acetate to the residue and wash the mixture with water and brine. EtOAc (EtOAc) 89% of the theoretical value) The following compounds were obtained analogously to the example LXVII: (1) 1-[(6/?,1〇^?,125&gt;2-cyclopropyl-5,6,7,8,9,10 -hexahydro-1〇12_dimethyl-6,10-曱 bridge-oxazole[4,5-ίΠ3]benzoazepine-4-7-yl]_2,2,2-trifluoro-ethanone

(2) 1-[(6义10/?,12幻-2-Cyclopropyl·5,6,7,8,9,1〇-hexahydro_1〇12 dimethyl-6,10-A Bridge-oxazole[5,44][3]benzoazepine_7_yl]_2,2,2 trifluoro-ethanone

Mass Spectrum (ESI+): m/z = 379 [Μ+Η] + (3) 1 - [(6/?,1 〇*S*)-2 -T-butyl-5,6,7,8,9 ,1〇-hexahydro-1〇,12,12 trimethyl-6,10·methyl bridge-oxazolo[4,5-i][3]benzoazepine-7-yl]_2,2, 2 trifluoro-ethanone

135590.doc •179· 1 2,2,2-trifluoro-1-[(6 and,1〇幻-5,6,7,8,9,1〇-hexahydro-1(),12,12 200927115 Trimethyl-2-(5-fluorenyl-pyrazine-2-yl)·6,10·methyl bridge-oxazolo[45i][3]benzone-7-yl]-ethanone

Ml,ll-trimethyl·1,2,3,4,5,6-hexahydro-2,6-methyl bridge·benzo[d]azepine·7_ alcohol, 6,11,11-trimethyl _ι,2,3,4,5,6·hexa-argon-2,6_a bridge-benzopyrene d] i -9-ol and 3,3,4·trimethyl-2,3,4 , 4a,9,9a-hexahydro-1H-indolo[244]pyridine-7-yield 2-(3-methoxy-nodoxy)-3,3-dimethyl-4-indenyl- Beta bottom. _ι_曱搭 (for preparation see J. Med. CTzem. 1997, Yang, 2928-2939; 47.5 g) Q in combination with 48% aqueous HBr (300 mL). The mixture was heated to reflux temperature and stirred at this temperature for 24 h. After cooling to ambient temperature, the precipitate was separated by filtration, washed with water and wet-purified with acetone. Next, the precipitate was dissolved in a mixture of 1 N aqueous NaOH and Ch 2 C 12 . The CH2CMa* was detached, dried (Na 2 S 〇 4) and concentrated. The residue was recrystallized from Et 〇Ac to provide 6,11,11-trimethyl-i,2,3,4,5,6-hexahydro-2,6-fluorene-benzo[d]nitrogen啐-9·Alcohol. The filtrate of the reaction mixture was combined with water and acetone phases (from washing and wet milling) and basified using concentrated aqueous ammonia. The 135590.doc • 180· 200927115 was extracted by CH2C12, and the combined organic extracts were dried (MgS 4) and the solvent was evaporated. The residue was purified by silica gel chromatography (EtOAc / MeOH / EtOAc (EtOAc): EtOAc: EtOAc: EtOAc: ,5,6-hexahydro 2,6-methyl bridge-benzo[d]azepine_7-ol and 3 3 4 trimethyl 2 3,4 4a,9,% hexahydro-1H-indole[ 2, lb] pyridine-7-ol. 6,11,11 monomethyl-123,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine, alcohol: _ yield: 5.2 g (13% of theory) 〇MS (ESI+) : m/z=232 [M+H] + 6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6_a bridge_ Benzo[(1]azepineol: Yield: 9.3 g (23% of theory) Mass Spectrum (ESI+): m/z=232 [M+H] + 3,3,4-trimethyl-2 ,3,4,4a,9,9a-hexahydro-1H-indolo[2,anthraceridinol: Yield: 4.2 g (10% of theory) ® mass spectrum (ESI+): m/z=232 [ M+H] +

Example LXIX

(1-Benzyl-allyl)-(2-methyl-allyl)-aminoformamidine tert-butylate Add NaH (60% in oil, 0.15 g) to (1-section) Base. Rare propyl 135590.doc -181 - 200927115 base)-T-butyl carbamic acid (for preparation see, for example, Ugly 7 2002; ;, 139_144; 〇.86 _Ν_methylpyrrolidine _(5 J) In the solution, the resulting mixture was stirred at room temperature for 3 Torr, followed by the addition of 3-bromo-2-mercapto-propene (0.38 mL). Stirring 5 "Moxibustion, adding brine and extracting the mixture with ethyl acetate. Drying (NajO4 The combined organic extracts were evaporated, and the residue was purified eluting eluting eluting eluting eluting : m/z = 3 〇 2 [M+H] + The following compounds were obtained similarly to the example LXIX: (1) 0-benzyl-dilyl)-(4-indolyl-pent-4-yl) -T-butyl carbamic acid

Mass Spectrum (ESI+) ·· m/z = 330 [M+H] + ??? 4-Methyl-pent-4-enyl methanesulfonate was used as an electrophile.

Example LXX 135590.doc -182- 200927115

Benzyl-4-methyl-2,5-di-ar-pyrrole-1-carboxylic acid tert-butyl [[1,3-1,3-(2,4,6-trimethyl) at room temperature under argon atmosphere Phenyl)_2·yamidyl]·•dichloro-(phenylmethylene)-(tricyclohexylphosphine)_钌(28 mg) is added to (1-benzyl-allyl)-( 2-methyl-allyl)-carbamic acid tributyl vinegar © (0.77 g) in toluene (5 〇 mL). The resulting mixture was heated to 6 ° C and at this temperature After stirring for 3 h, the solvent was evaporated and purified mjjjjjjjjjjjjjjjj ESI+) : m/z = 274 [M+H] + The following compounds are obtained in analogy to the example LXX: (1) 7-benzylmethyl-2,3,4,7-tetrahydro-azhen-l-carboxylic acid Third Ding

❹

Mass Spectrum (ESI+): m/z = 3 02 [M+H] + Instance LXXI

135590.doc -183- 200927115 1-Methyl-10-aza-tricyclo[7.4.1.0*2,7*]tetradec-2,4,6-triterpene trifluoromethanesulfonic acid (2.5 mL Addition to 7 volts 5-methyl-2,3,4,7-tetrahydro-azhen_1-carboxylic acid tert-butyl ester (〇3〇§) in dioxane (cooled in an ice bath) In a solution of 5 mL). The ice bath was removed and the solution was stirred at room temperature for $h. Then ice-cold water and an aqueous solution of K2C 3 were added and the mixture was extracted with ethyl acetate. The combined extracts were dried (NaaSCU), EtOAc evaporated eluting eluting

实例 Example LXXII

7-nodal group-6,7,9,10-tetraar argon_5H_6,1〇•methyl bridge-pyridyl[3 2_d]azin-8-one (diastereoisomer racemic mixture shown) Will be equipped with a stir bar, 2-pyryl-2-aza-bicyclo[3.3.1]nonane-3,6-dioxime (for preparation see 乂C/jew. iSoc·, Perh.n ·/, 1999 , ❹ 1157_1162; 0.80 g), a flask of NaAuCl4*2 H2O (30 mg), propargylamine (0.45 mL) and ethanol (5 mL) were heated at 100 ° C for 10 min under microwave irradiation. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexanehexane / ethyl acetate / methanol 6: 4:1). Yield: 0.52 g (56% of theory)

Example LXX1II

135590.doc -184· 200927115 7_Benzyl-5,6,7,8,9,10-hexahydro·6,10_methyl bridge_pyridine-indole--azepine (diastereomer shown) "Narrow race mixture" LiAlHdl in THF, 4.5 mL) was added dropwise to the 7-benzyl-6,7,9,l-tetrahydro-5Η-6,10-A cooled in an ice bath. A solution of the bridge pyrido[3,2-d]azepine-8-oxime (0.55 g) in THF (3 mL). The cooling bath was removed and the mixture was stirred at room temperature for 2 h. Ice cold water and 4 Μ hydrochloric acid (4 mL) were added and the mixture was further mixed for 15 min. The mixture was then basified with 4 M aqueous NaOH and the mixture was extracted with ethyl acetate. The combined organic extracts were dried <RTI ID=0.0>(Na2</RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> Yield: 0.16 g (32% of theory) The following compound is analogous to the example of LxxI]; I obtain: (1) 9-benzyl·3,5,9-triaza-tricyclo[6.3.1.0*2 ,6*]t-12(6),4-diluted (racemic mixture of diastereomers shown)

5 5 (ESI) : m / z = 254 [Μ + Η] + (2) 9-benzyl-4-mercapto-3,5,9 · triaza-tricyclic [6.3.1.0 * 2, 6*] -12(6), 4-diene (diastereomeric racemic mixture shown)

Mass Spectrum (ESI): m/z = 268 [Μ+Η] + 135590.doc -185- 200927115

Example LXXIV

2-benzyl-7,7-dibromo-2-aza-bicyclo[3.3.1]decane_3,6-diindole (diastereomeric racemic mixture shown) bromine 1.2 mL) solution in acetic acid (5 mL) was added to 2-benzyl-2-aza-bicyclo[3.3.1]nonane-3,6-dione (for preparation see 1/ (: heart) ^, Seto was used in a solution of -7, 1999, 1157-1 162; 3.05 g) in acetic acid (40 mL). The resulting solution was mixed for 2 h at room temperature. Then, the solution was poured into ice-cold water and The resulting mixture was extracted with EtOAc. EtOAcjjjjjjjjjjjjjj =400/402/404 (2 Br) [M+H] +

Example LXXV

9-nodal-3,5,9.diazepine-tricyclo[6·3.1·0*2,6*]t-12-2(6),4-diuret-10-ketone (not shown Azeotrope-like racemic mixture) Stir 2-benzyl-7,7-dibromo-2.aza-bicyclo[3.3.1]nonane-3,6-dione at room temperature (a non-pair A mixture of 2.50 g), trioxane (0.19 g) and ca. 7 ammonia in methanol (25 mL) was stirred overnight at room temperature. Next, the solution was concentrated and purified by silica gel chromatography (CH2Cl2 / MeOH 99:1 - 9:1) 135590.doc - 186 - 200927. Yield: 0.85 g (about 85% purity, 44% of theory). Mass Spectrum (ESI+): m/z = 268 [M+H] + The following compounds are obtained in analogy to the example LXXV: (1) 9-block base- 4-methyl-3,5,9-triaza-tricyclo[6_3.1.0*2,6*]dodecyl 2(6),4-dien-1-0-one (diastereoisomer shown) Racemic mixture

Use acetaldehyde instead of paraformaldehyde. Preparation of the final compound: Procedure A (described in Example 1 of Table 3)

[(2圮65&gt;10, hydroxy·6, ΐΐ, ιι_trimethyl-1,2,5,6-tetraar-4H-2,6-methyl bridge·benzo[d]azin-3-yl Phenyl-ketone will be 2-(1Η-p-triazol-bu)-tetrafluoroborate-1,1,3,3-tetramethylguanidine (155 mg; or hexafluorophosphate, ruthenium, Ν·,Ν••四曱基_〇_(7_azabenzotriazol-1-yl)锞) is added to benzoic acid (60 mg) and ethyldiisopropylamine (0 25 mL) in two gas The solution in the system (1 mL; DMF can also be used). The resulting solution was scrambled at ambient temperature for 15 min, then cooled in an ice bath. Add (2Λ,65&gt;6,11,11_三曱Base-12,3,4,5,6-hexahydro-2,6-anthracenyl-benzo[d]azepine-10-alcohol (〇.1() g) and warm the solution to room temperature and stir The mixture was concentrated under reduced pressure and EtOAc EtOAc EtOAc (EtOAc) ESI+) : m/z=336 [M+H] + Program B (described in Example 151 of Table 3)

(2 and, 6I?, 115&gt; 3_(3H-benzimidazole-5-carbonyl)_6,11-dimethyl-

Add 4 M NaOH aqueous solution (1 mL) to (2/?,6/?,11 magic-3-(31^benzimidazole-5-carbonyl)-6,11-dimercapto-1,2,3 , 4,5,6-hexahydro-2,6-methyl bridge-p- and [d]azetidine-8-carboxylic acid ethyl ester (〇.6〇g) in a solution of ethanol (3 mL). The resulting solution was stirred at a temperature. The solution was then slightly acidified (pH about 5) using 1 M hydrochloric acid and the obtained mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgS?4). Evaporation of the solvent <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> Said)

(2/?,6/?,llS)-3-(3H-benzimidazole-S-fraction f 1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzo[ 0]氙崎135590.doc -188- 200927115 Add 4-( 1H-benzotris-1 -yl) 4,13,3·tetradecyl fluorene (9〇mg) to (2/ ?,67?,115)-3-(311- stupid and sedative_5_ reneegal)_6, ιι_ dimethyl-1,2'3,4,5,6-hexahydro-2,6-A Bridge _benzo[[1]azepine_8-formic acid benzoic acid (0.10 g) and ethyldiisopropylamine (53 μ!^) in dimercaptocaramine (2 mL) in a solution. The resulting solution was stirred at temperature for 20 min, then diamine was added (40% in HzO '60 μΙ〇. The solution was stirred overnight. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (H2 /MeCN/NH3) The product was obtained as a solid. 〇 Yield: 55 mg (51% of theory) Mass (ESI+): m/z = 417 [M+H] + procedure D (as described in Example 172 of Table 3)

2,6-A bridge-benzo[d]azepin-3-yl]-(3H-benzimidazol-5-yl&gt;-methanone oxime at 50 ° C under a hydrogen atmosphere with 阮ni Ni ( 50 mg) treatment (2i?,6/?,llS)- 3-(3H-本弁味0 sitting-5-single base)-6,11-dimethyl-1,2,3,4,5, a solution of 6-hexanitro-2,6_ fluorene-benzo[d]azepine-8-carbonitrile (50 mg) in 1 hydrazine in methanol (5 mL) for 3 h. The filtrate was concentrated under reduced pressure EtOAc (m.). 375 [M+H] + 135590.doc -189- 200927115 Procedure E (described in Example 174 of Table 3)

-1,2,5,6-tetrahydro-4Η·2,6·methyl bridge·benzo[d) benzoxanth-6-yl-(6-methylazin-3-yl)-carboxamidine Palladium diacetate me), = r咏/Λτ, under argon atmosphere

[d] Azin-8-yl ester (0.30 g) in dimethyl decylamine (1 mL). The resulting mixture was stirred at 60 ° C for 20 h. After cooling to room temperature, brine was added and the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine and dried (EtOAc mjjjjjjjjjjjjjjjjj ) : m/z=349 [M+H] + Q Program F (described in Table 1 for Example 1*75)

3-(1Η-benzimidazole_5-carbonyl)-N-hydroxy 'nji trimethyl· 1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[3] Gas 吟-9-A lung is stirred at reflux temperature 3-(1Η-benzimidazole-5-carbonyltrimethyl-1,2,3,4,5,6-hexahydro-2,6_曱 bridge_ Benzo[4]azepine-9-indenecarbonitrile (〇.3〇light) 135590.doc -190- 200927115 and a solution of hydroxylamine (50% in water, 0.5 ml) in ethanol (5 mL) for 2 h. The title compound was obtained as a white foamy solid. mp.: EtOAc: EtOAc: +H] + Program G (described in Example 176 of Table 3)

(1H_benzimidazol-5-yl)-[6,11,11-trimethyl_9·(5-methyl-mouth, 2,4)oxadiazol-3-yl)·1,2, 5,6-tetra-argon-4Η-2,6-methyl bridge-benzo[d]azinyl]_ ketone Add acetic anhydride (0.1 mL) to 3-(1Η-stupidimide _5-carbonyl) -N-hydroxy-6,11,11-tridecyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine_ 9- formazan ( 0.15 g) in a solution of 2,4,6-trimethylpyridine (2 mL). The solution obtained at φ was stirred at ambient temperature for 1 h and then at 120. (: stirring for 3 h. V is up to / after JBL'. Reduce the mixture and reduce the residue in methanol (10 mL). Add concentrated aqueous ammonia solution (丨mL) and mix the solution at ambient temperature. The title compound was obtained as a white foamy solid. Yield: 0.15 g (95% of theory). : 111/2=442 [M+H] + Program H (described in Example 177 of Table 3) 135590.doc -191 - 200927115

3_(benzothiazol-6-carbonyl)-8-hydroxy-2,3,4,5-tetra-argon·1Η-2,6-methyl bridge-benzo[d]azepine-6-carbonitrile Acetic anhydride (43 μχ) was added to the ice bath to cool 3_(benzothiazol-6-yl)_8•transyl 2,3,4,5 tetrahydro-m_2,6_a bridge-stupid (4) nitrogen吟_6-Protonamine (40 mg) and ethyldiisopropylamine (5 〇μί) in a solution of di-methane (7) 5 © mL) Remove the ice bath and stir the solution at ambient temperature for 4 h ^ Another portion of trifluoroacetic anhydride (43 μί) and ethyldiisopropylamine (5 μμί) were added and the solution was stirred overnight. Methanol (1 mL) was added and the solution was evaporated. m. Yield: 18 mg (47% of theory) Mass Spectrum (ESI+): m/z = 476 [M+H] + Procedure 1 (as described in Example 1 of Table 3)

N-[3-(3H-benzimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzene And [d]azin-9-ylmethyl]-acetamide added triethylamine (38 μ! 〇 and acetic anhydride (26 μιη) to (9-aminomethyl· 6,11,11-three) Methyl-l,2,5,6-tetrahydro-4Η-2,6-methyl bridge·benzo[d]nitrogen 4 -3- 135590.doc -192- 200927115 base)-(3H-benzimidazole _ a suspension of 5-yl)·methanone (〇.1〇g) in acetonitrile (2 mL). The mixture was stirred at ambient temperature! h. Next, methanol (1 mL) was added and concentrated aqueous ammonia was added ( 5. 5 mL) and the resulting solution was re-supplied for 30 min. The solution was concentrated under reduced pressure. 66% of theory) Mass Spectrum (ESI+): m/z = 431 [M+H] + Procedure J (as described in Example 180, Table 3) © 03⁄43⁄4 [(2 and,6$)-10-hydroxy-6, 11,11-trimethyl-1,2,56_tetrahydro_4]^2,6-methyl bridge-benzo[d]glycid-3-yl]-(2-indolyl-cough _3+ _ base) _ A leisurely added boron tribromide (2 mL) to [(2 and, 6 magic-1〇-methoxy·61111 tridecyl-1,2,5,6- Tetrahydro-4Η·2,6-曱 bridge·benzodiazepine_3_yl]-(2-mercapto-furan-3-yl)-fluorenone (0.22 g) in dioxane (1 mL) The solution was stirred at ambient temperature for 2 h. Then water was added and the mixture was stirred for another 10 min. The organic phase was separated and the aqueous phase was extracted with di- methane. The combined organic phases were washed with brine and dried ( NajO4). The title compound was obtained from EtOAc EtOAc: EtOAc: EtOAc: Doc -193- 200927115

N-[3-(3H-benzimidazole_5-carbonyltrimethylhexafluoro-2,6-methyl bridge-benzo[d]azin-9-yl]-methanesulfonamide-triethylamine 38 gL) and A. calcined chlorine (21 μΙ〇 added to N-[3-(3H-benzimidazole-5-carbonyl)-6,ll,ll-trimethyl-1,2,3,4, 5,6-Hexahydro-2,6-methyl bridge-benzo[d]azepine-9-yl]-methyl-branched amine (50 mg) in a suspension of acetonitrile (1 mL). After h, the reaction was completed to give the title product which was further sulphated in an imidazole nitrogen. Methanol (1 mL) and concentrated aqueous ammonia (0.5 mL) were added and the mixture was stirred at room temperature overnight and then at 45. Stir for another 4 h. Concentrate the reaction mixture under reduced pressure and reverse phase HpLc (water /

The title compound was obtained as a white foamy solid. Yield: 2〇11^ (330/0 of theory) Mass Spectrum (ESI+): m/z=453 [M+H] + ® Procedure L (described in Example 183 of Table 3)

Dimethyl·1,2,5,6-tetra-argon-(3H-benzimidazol-5-yl)-(1〇_hydroxy_llu_: 4H-2,6-methyl bridge-benzo[d]nitrogen啐_3·Metmethamine-yl H10-methoxy-llu_di-p-[d]azepin-3-yl)-methanone was stirred at 80 ° C (3Η-benzimidazole_methyl-1 , 2,5,6-tetrahydro-4H-2,6-anthrace 135590.doc -194- 200927115 (0.10 g) in hydrobromic acid (2 mL, 48% in water) for 24 h. After the ambient temperature, the solution was concentrated under reduced pressure and the residue was purified eluted with EtOAc EtOAc EtOAc (EtOAc) [M+H] + program M (described in Example 83 of Table 3)

❹ (311-benzimidazol-5-yl)-[(25,6/?,111〇-1,8-dihydroxy-6,11-dimercapto-1,2,5,6-tetra-argon- 4Η·2,6-A bridge-benzo[d]azepin-3-yl]-methanone Ο Add sodium borohydride (50 mg) to (2&gt;S,6圪ll/?)-3- (3H-benzo-imidazole-5-carbonyl)-8-hydroxy-6,ll-dimethyl-3,4,5,6-tetrahydro-2H-2,6-methyl bridge-benzo[d] A solution of nitropyridin-1-one (50 g) in ethanol (3 mL). The mixture was stirred overnight at ambient temperature. Then, the solution was cooled in an ice bath and 1 HCl (0.5 mL) was added. After min, the mixture was concentrated and the residue was purified eluted with EtOAc EtOAc (EtOAc) Program N (described in Example 228 of Table 3)

135590.doc •195- 200927115 oxazol-5·yl)-l,2,5,6-tetra-argon-4H-2,6-methyl bridge-benzo[d]azepin-3-yl-methanone Sodium nitride (105 mg), NH4Cl (87 mg) and (2/?, 6-foot 115&gt; 3-(3H-benzimidazole-5-carbonyl)-6,ll-dimethyl-i,2,3 a mixture of 4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine-8-carbonitrile (0.30 g) in dimethylformamide (3 mL) at 100 ° Stir overnight at C. Next, add another portion of NaN3 (50 mg) and NH4C1 (40 mg) at 11 Torr. The mixture was stirred for a further 14 h. After cooling to ambient temperature, the mixture was diluted with water and MeCN and reversed. Purification by phase HPLC (MeCN/H20/NH3). Yield: 0·24 g (72% of theory) MS (ESI+): m/z=414 [M+H] + program 〇 Said)

(3H-benzimidazol-5-yl)-1(2/^,65)-8-(1-hydroxy_1.methyl-hexyl)-6,ll,ll-trimethyl-l,2 ,5,6-tetraar-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3-yl]-methylamine will l-[(2i?,6&lt;S)-3-(3H- Benzoxazole-5-carbonyl)_6,11,11-tridecyl·1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[[1] 吟- A solution of 8-yl]-ethanone (〇.1〇§) in tetrahydrofuran (1 mL) was added to an ice bath (about 〇.〇) for cooling

MeMgI (3 mol/L in Et2〇, 0.25 mL) in tetrahydrofuran (1 mL). Next, the cooling bath was removed and the mixing solution was stirred at room temperature for 5 h, then more MeMgI (3 mol/L in Et2〇, 0.25 mL) was added and at 135590.doc • 196- 200927115 5〇°C The solution was stirred for 4 h. After cooling in an ice bath, an aqueous solution of ΝΗ4α was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO.sub.4) and solvent was evaporated. The residue was purified by reverse phase HPLC (MeCN/H20). Yield: 26 mg (25% of theory) Mass Spectrum (ESI+): m/z = 418 [M+H] + Procedure P (for Example 2, Table 2; 52)

(1H-benzimidazol-5-yl) [(2/?,6/?,115)-6,11-dimethyl-8-oxime 1,2,4]oxazol-3-yl-1 ,2,5,6-tetraar-4H-2,6-methyl bridge-benzo[d]nitro 4-3-yl]-methanone triethyl orthoformate (4 mL) with (2/?, 6/?,115&gt;3-(1Η-benzoxazole_5-carbonyl)-oxime-hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2, A mixture of 6-methyl bridge _benzo[d]azepine-8-formamidine (0.25 g) was stirred at 1 Torr: 6 After cooling to room temperature, the mixture was concentrated and purified by reverse phase HPLC (water/MeCN/ The title compound was obtained as a white solid. mp.: ield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3 Example 2ό7)

Ν

135590.doc -197- 200927115 [(2/?,6/?,115&gt;)-7-Amino-8-methyl-based-6,11-dimethyl_12&lt;/: 必ι,Λ5,6 -tetrachloro-4-pyrene-2,6-methyl bridge-benzo[d]azepin-3-yl]-(3Η-benzimidazole_s_yl)methyl mesh at room temperature under a hydrogen atmosphere 〇% / carbon (1. 〇g) and (3h stupid ^^ oxazol-5-yl)-[(2i?,6/?,115&gt;8-methoxy-6,11-dimethyllocene 1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro 4-3-yl]-methanone 5〇(2) in decyl alcohol (20 mL) The mixture was filtered for 1 d. <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; +H] + program R (described in Example 270 of Table 3)

N (3H-benzimidazol-5-yl) 4(2^61^,115)-8-methoxy_6,u_dimethyl

7-fluoren-1-yl-I,2,5,6·tetra-argon-4H-2,6-methyl bridge-benzopyrene d]azepine_3_yl]_ ❹甲嗣 at ll〇°C Stirring [(2/^61115)-7-amino-8-methoxy_6,u_dimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzene And [d]azinium_3_yl]-(3H_benzimidazol-5-yl)-methanone (150 mg) and 2,5-dimethoxy-tetrahydrofuran (5 〇) in acetic acid (2 Solution in mL) for 3 h. After cooling to ambient temperature, the solution was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO.sub.4). Next, the solvent is removed to provide the title compound as a foamy solid. 135590.doc -198- 200927115 Yield: 73 mg (43% of theory) Mass (ESI+): m/z=441 [M+H] + Table 3

Example No. Chemical Name/Structure/Remarks Similar to Procedure Preparation Characterization 1 [(2F 65)-10-Hydroxy-6,11,11-trimercapto-1,2,5,6-tetrahydro-4H-2, 6-A bridge-benzo[d]azol-4-yl]-phenyl-fluorenone A mass spectrometry (ESI+): m/z = 336 [M+H]+ 2 (2-m-phenyl)- [(2 feet 65 &gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine-3- Base]-methanone?HO Cl A mass spectrometry (ESI^: m/z=370/372 (Cl) [M+H]+ 3 4-[(2i?,65&gt; 10-hydroxy-6,11,11 - Trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro 4-3-carbonyl]-nodoline OH ' ^νΛ〇υΝΗ2 0 A mass spectrometry ESI+): m/z=379 [M+H]+ 4 (3 benzobenzimidazole-5-yl)-[(2-re-65)-10-hydroxy-6,11,11-tridecyl-1, 2,5,6-tetrahydro-4 fluorene-2,6-methyl bridge-benzo[d]azin-4-yl]-fluorenone OH A mass spectrometry (ESI+): m/z=376 [M+H] + 135590.doc •199- 200927115

5 [(2i?,65&gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4- 3-based]-o-phenylidene-fluorenone OH A mass spectrometry (ESI+): m/z=350 [M+H]+ 6 [(2 foot 65)-10-hydroxy-6,11,11-trimethyl Base-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro-4-methyl)-(2-methoxy-phenyl]-fluorenone OH / A mass spectrum (ESI+): m/z = 366 [M+H] + 7 [(2, 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro- 4H-2,6-Methyl-benzo[d]azin-4-yl]-m-tolyl-fluorenone OH A mass spectrometry (ESI+): m/z=350 [M+H]+ 8 2-[ (2 feet 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-曱 bridge-benzo[d]nitrogen 4-3- Carbonyl]-benzonitrile OH μ 1A A mass spectrometry (ESI+): m/z=361 [M+H]+ 9 N- {3-[(2 feet 65)_ 10-hydroxy-6,11,11 - Tridecyl·1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro 4-3-carbonyl]-phenyl}-acetamide OH A mass spectrometry (ESI+) : m/z=393 [M+H]+ 135590.doc 200· 200927115

10 3-[(2i?,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d] Nitrogen 4-3-carbonyl]-benzonitrile OH A mass spectrometry (ESI+): m/z = 361 [M+H] + 11 [(2i?, 65)-10-hydroxy-6,11,11-trimethyl 1,2-,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]-(3-methoxy-phenyl)-methanone OH A Mass spectrometry (ESI+): m/z = 366 [M+H] + 12 [(2 s. 65 &gt; 10-hydroxy-6,11,11 -trimethyl-1,2,5,6-tetrahydro-4 Η- 2,6-A bridge-benzo[d]nitro 4-3-yl]-p-tolyl-carbazide OH A mass spectrometry SI+): m/z=350 [M+H]+ 13 4-[(2 Foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine-3-carbonyl] -benzonitrile OH A mass spectrometry (ESI+): m/z = 361 [M+H]+ 14 [(2,6,10-hydroxy-6,11,11-trimethyl-1,2,5,6 -tetrahydro-4H-2,6-anthracenyl-benzo[d]azepine-4-yl]-(4-decyloxy-phenyl)-oxime OH^n1Cl0. A mass spectrometry (ES〇: m /z=366 [M+H]+ 135590.doc 201 - 200927115

15 N- {4-[(2 foot 65)_ 10-hydroxy-6,11,11-trimethyl-l,2,5,6-tetrahydro-4H-2,6- 曱 bridge-benzo[ d] hydrazin-3-carbonyl]-phenyl}-acetamide OH Η A mass spectrum (ESf): m/z = 393 [M+H] + 16 [(2 s. 65) -10- hydroxy-6, 11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]azepin-3-yl]-[4-(2,2,2 -Tris-1--1-yl-1-indolyl-ethyl)-phenyl]-methanone A mass spectrometry (ESI+): m/z = 448 [M+H] + 17 [(2 &, 65)- 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen+3-yl]-(2-A -3H-benzimidazol-5-yl)-methanone OH A mass spectrum (ESt): m/z = 390 [M+H] + 18 (1 Η-benzimidazol-4-yl)-[(2 Foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-anthracenyl-benzo[d]azepin-3-yl] -methanone A mass spectrometry ^ m): m/z = 376 [M+H] + 19 [(2 足6S&gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetra Hydrogen-4H-2,6-fluorene bridge-benzo[d]nitro 4-3-yl]-(1-indolyl-1H-benzimidazol-5-yl)-methanone OH \ A mass spectrometry (ESI+) : m/z=390 [M+H]+ 135590.doc -202- 200927115

20 (2,3-Dihydro-benzo[1,4]dioxine-6-yl)-[(2F 65&gt; 10-hydroxy-6,11,11-trimethyl-1, 2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]-methanone OH ^^00 A mass spectrum (ESI+): m/z=394 [M +H]+ 21 (3H-benzotriazol-5-yl)-[(2 foot 65)-10-hydroxy-6,11,11-tridecyl-1,2,5,6-tetrahydro- 4H-2,6-anthracene-benzo[d]nitro-4-methyl]-fluorenone OH A mass spectrometry (ESI+): m/z=377 [M+H]+ 22 [(2/?,65&gt ; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]azul-3-yl]-(4 -piperidinyl phenyl-phenyl)-formaldehyde OH ^nX (XO A mass spectrometry (ESI+) m/z = 433 [M+H] + 23 [(2/?,65&gt; 10-hydroxy-6,11 ,11-tridecyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]-[4-(4-indolyl-slightly σ秦-1·ylmercapto)-phenyl]-formaldehyde A mass spectrometry (ESI+): m/z=448 [M+H]+ 24 [(2/?,65&gt; 10-hydroxy-6,11 ,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]azepin-3-yl]-(4-morpholin-4-ylindole --phenyl)-fluorenone OH A mass spectrometry (ESI+): m/z = 435 [M+H]+ 135590.doc 203 - 200927115

25 [(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4- 3-yl]-(4-morphin-4-yl-phenyl)-methylhydrazine OH A mass spectrometry (ESI+): m/z=421 [M+H]+ 26 [(2/?,65)-10 -hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η·2,6-anthracenyl-benzo[d]azepine-4-ol]-(4-pipeper °Qin-1-yl-phenyl)-methyl S with OH k^NH A mass spectrometry (ESI+) m/z=420 [M+H]+ The coupled product was obtained from procedure 4- from 4-(4-carboxy-benzene Base)-piperazine-1-decanoic acid tert-butyl ester obtained. The third butyl ester was cleaved after using the conditions described in Example XXVII. 27 N-{2-Fluoro-4-[(2-foot 65&gt; 10-hydroxy-6,11,11-trimethyl-l,2,5,6-tetrahydro-4H-2,6-anthracene bridge- Benzo[d]nitrogen 4-3-indolyl]-phenyl}-acetamidamine OH Η A mass spectrometry (ESI+): m/z=411 [M+H]+ 28 1 - {4-[(2 feet 65&gt; 10-hydroxy-6,11,11-tridecyl-l,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitro 4-3-carbonyl]-benzene }--ethanone OH A mass spectrum (ESI+): m/z = 378 [M+H]+ 135590.doc 204- 200927115

29 5-[(2i?,65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d] Nitrogen 4-3-carbonyl] benzhydryl-1,3-diphos-benzo[rho]°m-2 -嗣OH \ A mass spectrometry (ESI+): m/z=406 [M+H]+ 30 3- [(2 feet 65 &gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3- Carbonyl]-benzoic acid oxime ester OH A mass spectrometry (ESI+): m/z = 394 [M+H]+ 31 [(2/?,65)-10-hydroxy-6,11,11-tridecyl- 1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro-3-yl]-(1Η-吲〇多-6-yl)-methanone OH A mass spectrometry (ESI+): m/z=375 [M+H]+ 32 [3·B-Ket-4-(ntbp-bit-1)-phenyl]_[(2/?,65)-10 -hydroxy·6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-fluorene bridge·benzo[d]nitrogen 4_3·yl]-methanone 0H 0 A mass spectrometry (ESI+): m/z = 457 [M+H]+ 33 6-[(2i?,65&gt;10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro- 4Η-2,6-曱 bridge-benzo[d]nitrogen 4-3-carbonyl]-1,3-diode-σ引α朵-2-嗣0Η A mass spectrometry (ESI+): m/z=391 [ M+H]+ 135590.doc -205 - 200927115

34 7-[(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6·tetrahydro_4Η·2,6_曱 bridge-benzo[d]nitrogen唓-3-carbonyl]I methyl-3H-indole-4-one OH 0 A mass spectrometry (ESI&quot;): m/z=418 [M+H]+ 35 [(2Λ,6β-10-hydroxy- 6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-stupid [d]aza 4-3-yl]-[3-indolyl-4 -(.Bilo bites-1-amino)·phenyl]-曱嗣OH ^^0;〇0 A mass spectrum (ESI+): m/z=447 [M+H]+ 36 4-[(2i? ,65&gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-anthracenyl-benzo[d]nitrogen 4-3-carbonyl]- Ν-mercapto-benzylamine 办 1Cv ΗΝχ A mass spectrometer SI+): m/z=393 [M+H]+ 37 4-[(2i?,65)-l 0-hydroxy-6,11,11 -trimethyl-1,2,5,6-tetrahydro-4Η-2,6-anthracenyl-benzo[d]azepine-3-carbonyl]-N,N-didecyl-benzylguanamine A mass spectrometry (ESI+): m/z = 407 [M+H] dec 38 3-[(2 s 65 &gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro) -4H-2,6-曱 bridge-benzo[d]azepine-3-carbonyl]-oxime, Ν-dimethyl-benzylamine oxime A mass spectrometry (ESI+): m/z=407 [M+H ]+ 135590.doc -206- 200927115

39 3-[(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H_2,6-methyl bridge-benzo[d]azepine- 3-carbonyl]-N-methyl-benzylamine A mass spectrum (ESf): m/z = 393 [M+H] + 40 [(2i?, 65)-10-hydroxy-6,11,11- Methyl-1,2,5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azepine-4-phenyl]-[3-((i?)-2-decyloxy) Mercapto-pyrrolidine-1-carbonyl)-phenyl]-methanone A mass spectrometry (ESI+): m/z = 477 [M+H] + 41 3-[(2 s. 65 &gt; 10-hydroxy-6,11 ,11-tridecyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitrogen 4-3-carbonyl]-nodal amine OH ύ^ΝΛ〇ΛΝΗ2 A Mass spectrometry (ESI+): m/z = 379 [M+H] + 42 3- gas-5-[(2, 65)-10-hydroxy-6,11,11-tridecyl-l,2,5, 6-Tetrahydro-4Η-2,6-anthracenyl-benzo[d]azetidine 4-3-carbonyl]-benzoic acid methyl ester OH Cl A mass spectrometry (ESI+): m/z=428/430 (CI) [M+H]+ 43 3-Fluoro-5-[(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6 - 曱 bridge-benzo[d]nitro 4-3-carbonyl]-benzoic acid methyl ester OH FA mass spectrometry (ESI+): m/z = 412 [M+H]+ 135590.doc -207- 200927115

44 6-[(2/?,6^)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[ d]aza 4-3-carbonyl]-3,4-dihydrooxin-2-one oxime Η A mass spectrometry (ESr): m/z=406 [M+H]+ 45 benzothiazole-5-yl- [(2/?,65)-10-hydroxy-6,ll,ll-trimethyl-l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine -3-yl]-methanone A mass spectrometry (ESI+): m/z = 393 [M+H]+ 46 benzothiazole-6-yl-[(27^,65&gt;10·hydroxy-6,ll, Ll-trimethyl-l,2,5,6·tetrahydro 4H-2,6-fluorene bridge-benzo[d] gastrien-3-yl]-fluorenone oxime A mass spectrometry (ESI+): m/z =393 [M+H]+ 47 8-[(2i?,65&gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-曱Benzene-benzo[d]nitro 4-3-carbonyl]-3,4-dihydro-1 benzobenzo[s,[1,4]diazepine-2,5-dione OH 0 A mass spectrometry (ESI+) : m/z=434 [M+H]+ 48 [(2 feet 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6 -曱桥-Benzo[d]azac-3-yl]-(4-decylamino-phenyl)-methanone OH 1 A mass spectrometry (ESI+): m/z=365 [M+H]+ 135590.doc -208- 200927115

49 [(2i?,6&lt;S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d] Nitrogen 4-3-yl]-(1Η-吲.5-yl)-曱嗣OH Η A mass spectrometry (ESI,·· m/z=375 [M+H]+ 50 4-[(2i?, 65&gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-anthracenyl-benzo[d]nitrogen 4-3-carbonyl]-benzene Hydrazine decanoate OH /° A mass spectrometry (ES〇: m/z=394 [M+H]+ 51 (3沁benzimidazol-5-yl)-(8-hydroxy-6-mercapto-1,2 ,5,6-tetrahydro-4Η-2,6-anthracenyl-benzo[d]azin-4-yl)-methanone A mass spectrometry (ESI+): m/z=348 [M+H]+ 52 (3H-benzimidazol-5-yl)-[(2 foot 6 ft 115)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6- A bridge-benzo[d]azol-4-yl]-methanone η. A mass spectrometry (ESf): m/z=362 [M+H]+ 53 (3Η_benzimidazole-5-yl H ( 21S,61S,ll/?)-8-hydroxy-6,ll-dimercapto-l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3 -yl]-methanone A mass spectrometry (ESI+): m/z=362 [M+H]+ 135590.doc 209- 200927115

54 (3H-benzimidazol-5-yl)-(8-hydroxy-6,11-dimethyl-l,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d N,4-3-yl)-methanone A mass spectrometry (ESI+): m/z=362 [M+H]+ 55 (3H-benzimidazol-5-yl)-(8-hydroxy-l,2, 5,6-Tetrahydro-4H-2,6-anthracene-bromo-[d]azin-4-yl)-methanone η. MA A mass spectrometry (ESf): m/z = 334 [M+H]+ 56 (3Η-benzimidazol-5-yl)-(6,8-dihydroxy-11,11-dimethyl-1,2 ,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]azaki-3-yl)·formamidine A mass spectrometry (ESI+): m/z=378 [M+H]+ 57 (3H-benzimidazol-5-yl)-(6-hydroxydimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3- Methyl ketone A mass spectrometry (ESI+): m/z = 362 [M+H] + 58 (3H-benzimidazol-5-yl)-(8-hydroxy-6,11,11-trimethyl- 1,2,5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azin-3-yl)-methanone A mass spectrometry (ESI+): m/z=376 [M+H ]+ 59 (3H-benzimidazol-5-yl)-(9-hydroxy-6,11,11·trisyl-1,2,5,6-tetrahydro-4Η-2,6-曱 bridge- Benzo[d]azepin-3-yl)-methanone A mass spectrometry (ESI+): m/z=376 [M+H]+ 135590.doc -210- 200927115 ❹

(3H-benzo&quot;methane-5-yl)-(l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl)-oxime Ketone-------- 60 03⁄43⁄4 A Mass Spectrum (ESf): m/z=318 [M+H]+ (3H·benzimidazole_5·yl)_[(25,6 and)-8- Methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]-嗣0 ----- 61 A mass spectrometry (ESI+): m/z=404 [M+H]+ The compound was resolved after HPLC analysis of the racemic mixture by palm phase HPLC or by using the palm phase HPLC. Obtained by the enantiomerically pure starting material obtained from the racemic mixture. (3Η·benzimidazole _5_yl)-[(2 foot 65&gt;8-decyloxy-6,9,11,11 tetradecyl-1,2,5,6-tetrahydro-4Η_2,6- A bridge of benzo[d]ylidene-3-yl]indene steel 0 62 A mass spectrometry (ESI+): m/z=404 [M+H]+ ---- The compound is analyzed by HPLC The racemic mixture is obtained after use or by using an enantiomerically pure starting material obtained by fractional phase HPLC analysis of the racemic mixture. ~ - - (3H-benzimidazol-5-yl)- [(2/?,65)-9-methoxy·6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[ d] gasside-3·yl]-a class 63 °Χ^ν1Ό:&gt; A mass spectrum (ESI+): m/z=404 [M+H]+ --- The compound is analyzed by HPLC on the palm phase. The racemic mixture is obtained after use or by using an enantiomerically pure starting material obtained by resolution of the racemic mixture with palm phase HPLC. 135590.doc -211 - 200927115 Ο ❹ 64 (3Η-benzimidazole-5-yl )-[(2 and 6/〇-9-methoxy-6,8,11,11-tetradecyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-stupid [d]azacrid-3-yl]-methylamine compound is used after parsing the racemic mixture by palm phase HPLC or by using Obtained by phase HPLC analysis of the enantiomerically pure starting material obtained from the racemic mixture. A mass spectrum (ESf): m/z = 404 [M+H] + 65 (3H-benzimidazol-5-yl)-[( 2i?,65)-8-hydroxy-6,9,11,11-tetradecyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4- The 3-yl]-methanone compound is obtained after resolution of the racemic mixture by palm phase HPLC or by the use of an enantiomerically pure starting material obtained by resolution of the racemic mixture with palm phase HPLC. ESI+): m/z = 390 [M+H]+ 66 (3H-benzimidazol-5-yl)-[(2&gt;?,6/?)-8-pyridyl-6,9,11,11 -Tetramethyl-1,2,5,6-tetraar-4H-2,6-methyl bridge-benzo[d]azol-4-yl]-methanone field ^ compound in the use of palmar phase HPLC Obtained after resolution of the racemic mixture or by using an enantiomerically pure starting material obtained by resolution of the racemic mixture with palm phase HPLC. A mass spectrum (ESf): m/z = 390 [M+H] + 135590 .doc 212- 200927115

67 (3H-benzimidazol-5-yl)-[(2 foot 65)-9-hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro·4Η-2 , 6-A bridge-benzo[d]azin-3-yl]-fluorenone mV) compound is used to resolve the racemic mixture after HPLC with palmar phase or by using analytical HPLC Obtained by the enantiomerically pure starting material obtained by spinning the mixture. A mass spectrometry (ESI+): m/z = 390 [M+H] + 68 _' 69 (3H-benzimidazol-5-yl)-[(2&amp; 6Λ)-9-hydroxy-6,8,11, 11-tetradecyl-1,2,5,6-tetrahydro-4Η-2,6-methyl-bridged benzo[d]nitrogen+3-yl]•anthracene compound was analyzed by using palmar phase HPLC This is obtained after spinning the mixture or by using an enantiomerically pure starting material obtained by resolution of the racemic mixture with palm phase HPLC. A mass spectrum (ESf): m/z = 390 [M+H] + benzimidazol-5-yl)-(6,8,11,11-tetramethyl-1,2,5,6-tetrahydro- 4Η-2,6-曱 bridge-benzo[d]azepin-3-yl)_曱嗣A mass spectrometry (ESr): m/rf74 [M+H]+ 70 (3H-benzometic-5- ()-(8-fluoro-6,11,11-dimethyl-l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azin-3-yl) -Metformin A mass spectrometry (ES〇: m/z=378 [M+H]+ 71-一^(3H-benzimidazol-5-yl)-(9-ylamino-8-methoxy-6, 11,1,trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl)-methanone A mass spectrometry (ESI+): m /z=406 [M+H]+ ___--- 13559〇d〇c -213 200927115

72 (3H-benzimidazol-5-yl)-(8,9-dimethoxy-6,11,11-tridecyl-1,2,5,6-tetrahydro-4H-2,6- A bridge-benzo[d]azol-4-3-yl)-fluorenone A mass spectrometry (ESI+): m/z=420 [M+H]+ 73 (3H-benzimidazol-5-yl)-(8 -hydroxy-9-decyloxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge·benzo[d]nitro 4-3-yl -Metketone A mass spectrometry (ESC): m/z = 406 [M+H] + 74 (3H-benzimidazol-5-yl)-[(2 foot 65)-9-methoxy-6,ll ,l 1-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]azin-4-yl]-fluorenone A mass spectrometry (ESI+): m /z=390 [M+H]+ 75 (3H-benzimidazol-5-yl)-(8-chloro-6,11,11-tridecyl-l,2,5,6-tetrahydro-4H -2,6-anthracene-benzo[d]azin-4-yl)-methanone A mass spectrometry (ESI+): m/z=394/396 (Cl) [M+H]+ 76 (3H-benzene And imidazol-5-yl)-[(2 foot 65)-10-decyloxy-6,11,11-trimethyl-1,2,5,6·tetrahydro-4H-2,6- 曱 bridge -Benzo[d]aza 4-3-yl]-methanone A mass spectrometry (ESI+): m/z=390 [M+H]+ 135590.doc 214- 200927115 ❹ ❹ 77 -------- ^(3H-Benzamidazol-5-yl)-(6,11-dimethyl-1,2,5,6-tetrahydro-4H_2,6-methyl bridge-benzo[d]nitrogen 4-3- Base)-carbamidine compound is a racemic mixture of the pure diastereomers shown . ---- A mass spectrometry (ESI&quot;): m/z^346 [M+H]+ 78 (3H-benzimidazol-5-yl)-(7-hydroxy-6,11,11-trimethyl -1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]azepin-3-yl)-methanone A mass spectrum (ESf): m/z = 376 [M+ H]+ 79 (3Η-benzimidazol-5-yl)4(25,6^)-8-hydroxy-6,ll,ll-trimethyl-l,2,5,6-tetrahydro-4H- 2,6-A-benzo-[d]nitrogen 4·_3_yl]-carbamidine A mass spectrometry (ESf): m/z=376 [M+H]+ 80 (3Η-benzoxazole-5- Base)-[(2 foot 65)-8-carbyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d] Nitrozin-3-yl]-formamidine A mass spectrometry (ES〇: m/z=376 [M+H]+ 81 [(2,6,10-yl-trimethyl-1 256_tetrahydro-4Η_2, 6-A bridge-benzo[d]azepine_3_yl]-(3_methyl-3H-benzomidine. sit-5-yl)_methyl mesh OH ^----- A mass spectrometry (ESf ): m/z=390 [M+H]+ 135590.doc 215- 200927115

Ο 82 (3Η-benzimidazol-5-yl)-[(2 foot 6^-6,11,11-trimethyl-1,2,5,6-tetrahydro-4, 2,6-methyl bridge -Benzo[(1]azol-4-yl]-methanone This compound is obtained after resolution of the racemic mixture by palm phase HPLC or by using a racemic mixture for palm phase HPLC. Obtained as a pure starting material. A mass spectrometry (ESI+): m/z=360 [M+H]+ 83 (3Η-benzimidazol-5-yl)-[(2&lt;5,6 ft1 li?) -l,8-Dihydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]- Formazan OH Μ mass spectrometry (ESf): m/z = 378 [M+H]+ 84 (2 feet 6 ft 115 &gt; 3_(3H-benzimidazole-5.carbonyl)-6,11-dimethyl-1 ,2,3,4,5,6-hexahydro-2,6-anthracene-benzo[[1] gas 吟-8-甲猜 A mass spectrometry (ESI*): m/z=371 [M+H ]+ 85 ---—^ (3Η-benzimidazol-5-yl)-(6,11-diethyl-8-hydroxy-1,2,5,6-tetrahydro---2,6- The fluorenyl-benzo[[1]azama-3-yl)-fluorenone compound is a racemic mixture of the indicated diastereomers. A mass spectrum (ESf): m/z = 390 [ M+H]+ &gt;35590.doi •216· 200927115 86 -------1 87 (State-benzimidazol-5-yl)-(6,11-diethyl-8-hydroxy-1 , 2,5,6-tetrahydro-criminal-2 6_甲桥_benzoazaindole_3_yl)-formamidine compound is a racemic mixture of the indicated diastereomers. A mass spectrometry (ESI^: m/z=390 [M +H]+imidazolium-5-yl)-(6-ethyl-8-carbyl-11-carboindole, 2,5,6·tetrahydro-4Η-2,6-fluorene bridge-benzo [d]azin-3-yl)-methyl compound is racemic mixture of the indicated diastereomers _______ ^7 ° A mass spectrum (ESf): m/z = 376 [M+H]+ 88 1 stupid imidazolium '5_yl)-(8_ylamino-6-propyl-(4)'6, gas-4H-2,6-methyl bridge-benzo[OR 4-3-yl)-methanone A mass spectrometry (ESI+): m/z = 376 [M+H]+ 89 T-carbazin-5-yl)-(6·ethyl-8-pyridyl-11,11-,2,5,6-four Argon-4H-2,6-methyl bridge·benzo[d]azin-3-yl)-methanone A mass spectrum: m/z=390 [M+H]+ 135590.doc •217- 200927115

❹ 90 (3H-benzimidazol-5-yl)-(6-ethyl-8-hydroxy-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]nitrogen 4-3-yl)-methanone h〇^n1〇c&gt; A mass spectrometry (ESI+): m/z=362 [M+H]+ 91 (2 feet, 6 feet, 115)-3-(3H-benzimidazole -5-carbonyl)-6,11-dimercapto-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azetidine-8-decanoate扬1α:&gt; 0 A mass spectrum (ESI+): m/z = 418 [M+H]+ 92 benzox. Sodium 6-yl-(8-carbyl-6-methyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitrogen 4-3·yl)- Methyl ketone A mass spectrometry (ESI+): m/z = 365 [M+H]+ 93 (2i?, 65)-3-(3H-benzimidazole-5-carbonyl)-6,11,11-tridecyl -1,2,3,4,5,6-hexahydro-2,6-anthracenyl-benzo[[1]azepine-10-carbonitrile N feNXa&gt; A mass spectrometry (ESI+): m/z=385 [M+H]+ 94 3-(Benzene °°°-6- ing)-8-yl-based-2,3,4,5·tetrazine·1 Η_2,6-曱 bridge-benzo[ d] nitrogen 4-6-methyl decanoate is a human. 1 The compound may also be 8-ethoxycarbonyl-2,3,4,5-tetrahydro-lH-2,6-anthracene-benzo[d] Methyl hydrazine-6-carboxylate was obtained by treating the guanamine coupling product with K2C03 in methanol to remove the acetamino group from the phenolic oxygen. A mass spectrometry (ESI+): m/z = 409 [M+H]+ 135590.doc •218· 200927115

(2i?,6S)-3-(1 Η-benzimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6 -A bridge-benzo[d] nitrogen 4-10-decanoate 95 96

3-(1Η-benzimidazole-5-carbonyl)-6,11,11-trimethyl-l,2,3,4,5,6-hexahydro-2,6-anthracene-benzo[d Nitrogen -9-

3-(1Η-benzimidazole-5-carbonyl)-6,ll,ll-trimethyl-l,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d Azine-9-ethyl formate

(3H-benzimidazol-5-yl)-(1-indolyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradec-2,4,6-triene-11-yl -Methyl ketone mass spectrometry (ESI+): m/z = 432 [M+H]+ MS (ESI+): m/z=385 [M+H]+ MS (ESI+): m/z=432 [M+H ]+ 98

Mass Spectrum (ESI+): m/z = 346 [M+H] + (3H-benzimidazol-5-yl)-(4-decyloxy-9-aza-tricyclo[6.3.1.0*2,7 *]12-2,4,6-triene-9-yl)-曱99

Mass spectrometry (ESI+): m/z = 334 [M+H]+ 135590.doc -219- 200927115 ❺ ❹ 100 (3H-benzo-)-salt-5-yl)-(4-carbyl-9-yl) Tricyclo[6·3 · 1.0*2,7*]t-12-2,4,6-triene-9-yl)-曱蜩H. Gamma mass spectrometry (ESI+): tn/z=320 [M+H]+ 101 [(2 feet 65)-4-1〇-hydroxy-6,11,11-trimethyl-1,2,5,6 · Tetrahydro- 4 Η·2,6-methyl bridge-benzo[d]azepine-3-carbonyl]- benzoic acid OH (^Λ〇γ〇Η 0 compound is similar to the procedure Α using terephthalic acid single Tributyl ester was synthesized as a coupling partner. Subsequently, the third butyl ester functional group was cleaved using tri-gas acetic acid in di-methane. A Mass Spectrometry (ESI+): m/z = 380 [M+H] + 102 (3Η Benzimidazol-5-yl)-[(2/?,65)-6,11,11-tridecyl-9-phenyl 1,2,5,6-tetrahydro-4H-2,6- A bridge-benzo[d]azin-3-yl]-methanone A mass spectrometry (ESI+): m/z=436 [M+H]+ 103 (3H_benzimidazole·5-yl)-(6 -methoxy-1U1 _dimethyl-1,2,5,6-tetrahydro-411-2,6-methyl bridge-benzo[&lt;1]azaki-3-yl)-methyl/〇 A mass spectrum (ESf): m/z = 376 [M+H]+ 135590.doc 220- 200927115

[(2 feet 65)-10-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4 -3-yl]-(2-methyl-c-butyl-3-yl)-indole

Mass Spectrum (ESI+): m/z = 354 [M+H] + (8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzene And [d]azin-3-yl)-phenyl-methanone 105

Mass Spectrum (ESI+): m/z = 322 [M+H] + (8-hydroxy-6, ll-dimethyl-l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzene And [d]nitrogen α-octyl-3-yl)-o-tolyl-fluorenone

[(2 feet 6 feet 11 i?)-8-methoxy-6,11-dimethyl-l,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d] Nitrogen 4-3-yl]-0 is more than '^-3-yl-carbamidine

[(2Λ,6/?,11 methoxy-6,11-dimethyl-l,2,5,6·tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine-3 -yl]-(2-decyl-phenyl)-indole mass spectrometry (ESI+): m/z=336 [M+H]+ MS (ESI+): m/z=337 [M+H]+ ESI+): 108

A m/z=381 [M+H]+ [(2 feet 6 feet 1 li?)-8-methoxy-6,11-dimethyl-l,2,5,6-tetrahydro-4H- 2,6-anthracene-benzo[d]nitro-4-methyl]-o-phenylene-fluorenone

Mass Spectrum (ESf): m/z = 350 [M+H]+ 135590.doc -221 - 200927115

Furan-2-yl-[(2 foot 6 foot 11/?)-8-methoxy-6,11-dimethyl·1,2,5,6·tetrahydro-4H_2,6-anthracene-benzene And [d] nitrogen 4-3-yl]-fluorenone

[(2 feet 6 feet 11 i?)-8-methoxy-6,11-dimethyl-l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d] Nitrogen &lt;4-3-yl]-(3·methyl-°夫°南_2-yl)-曱网

[(2i?,6i?,l li?)-8-hydroxy-6,11-dimethyl-l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d] Nitrogen 4-3-ylH3-methyl-Df-am-2-yl)-carboxamidine

Furan-2-yl-[(2i?,6i?,lli?)-8-hydroxy-6,11-dimercapto-1,2,5,6-tetrahydro-4Η-2,6·曱 bridge- Benzo[d]azepine-4-3-yl]-methanone Mass Spectrum (ESI+): m/z=326 [M+H]+ MS (ESI+): m/z=340 [M+H]+ MS (ESI) ^: m/z=326 [M+H]+ 113 Ο

Mass Spectrum (ESI+): m/z = 312 [M+H]+ [(2i?,6/?,11 i?)-8-hydroxy-6,11-dimethyl-1,2,5,6- Tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3-yl]-° ratio 114 pyridine-3-yl-fluorenone

Mass Spectrometry (ESf)·· m/z=323 [M+H]+ 135590.doc 222- 200927115

115 [(2i?,6i?,l li?)-8-hydroxy-6,11-dimethyl-l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d ]azin-3-yl H2-decyl-phenyl)-methanone ο 〇,,νΓ〇UA mass spectrum (ESI+): m/z=367 [M+H]+ 116 [(2 feet 65)-10 -hydroxy-6,11,11-tridecyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]-(1H-吲C-2-yl)-曱813⁄4 0H A mass spectrum (ESI+) m/z=375 [M+H]+ 117 (4-aminomercapto-phenyl)-[(2Λ,65)-10-hydroxyl -6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benz[d]gas-3-yl]•carboquinone 0H ^νΛ1ΧΝη2 acid The coupling partner is 4-(t-butoxycarbonylamino-methyl) which is released from the third butoxycarbonyl residue after treatment with trifluoroacetic acid in dioxane to form the indoleamine. Benzoic acid. A mass spectrum (ESI+): m/z = 365 [M+H] + 118 [(2, 65)-10-hydroxy-6,11,11-tridecyl-1,2,5,6-tetrahydro- 4Η-2,6-A bridge-benzo[d]azepine-4-yl]-(1Η-吲°-3-yl)_ formazan 0H A mass spectrometry (ESI+): m/z=375 [M +H]+ 135590.doc 223- 200927115

119 (4-Diethylaminomethyl-phenyl)-[(2/?,65)-10-hydroxy-6,11,11-tridecyl-1,2,5,6-tetrahydro- The 4H-2,6-methyl bridge-benzo[d]aza 4-3-yl]-methanone OH compound was isolated as a trifluoroacetate salt. A mass spectrum (ESI+): m/z = 421 [M+H] + 120 [(2/?,65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetra Hydrogen-4H-2,6-methyl bridge-benzo[d]nitro 4-3-yl]-(4-0 than carboxymethyl-phenyl)-formamidine OH compound is in the form of trifluoroacetate Separation. A mass spectrometry (ESI+): m/z = 419 [M+H] + 121 (3,5-dimethyl-isoxazol-4-yl)-[(2/?,65)-10-hydroxy-6 ,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitro-4-ol]-methanone OH A mass spectrometry (ESI+) : m/z=355 [M+H]+ 122 1 - {4-[(2 feet 65)_ 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro- 411-2,6-曱 bridge-benzo[(!]nitro 4-3-carbonyl]-2-decyloxy-benzyl}-pyrrolidin-2-one OH 0 1 A mass spectrometry (ESI+): m/z=463 [M+H]+ 123 [(2i?,65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6 - A bridge-benzo[d]azin-4-yl]-(4-»myzol-1-ylindenyl-phenyl)-methanone compound is isolated as a trifluoroacetate salt. A mass spectrometry (ESI+ ): m/z=416 [M+H]+ 135590.doc -224- 200927115

124 (1,5-Dimethyl-1H-pyrazol-3-yl) 4(2^6^-10-hydroxy-6,11,11-tridecyl-1,2,5,6-tetrahydrol -4H-2,6-曱 bridge-benzo[d]azepin-3-yl]-fluorenone OH feV- \ A mass spectrometry (ESI+): m/z=354 [M+H]+ 125 N-{ 4-[(2 foot 65 &gt; 10-hydroxy-6,11,11-trimethyl-l,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d] nitrogen 4- 3-carbonyl]-benzyl}-benzylguanamine OH 0 A f tf (ESI+): m/z = 469 [M+H] + 126 [(2/?,6S)-10-hydroxy-6,11, 11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitrogen&lt;4-3-yl]pyridin-4-yl-fluorenone OH A mass spectrum (ESP): m/z = 337 [M+H] + U 127 [(2/?,65&gt; 10-hydroxy-6,11,11-tridecyl-1,2,5,6-four Hydrogen-4H-2,6-anthracenyl-benzo[d]azin-4-yl]-acridin-3-yl-methanone OH A mass spectrum (ESf): m/z = 337 [M+H] + 128 [(2i?,65&gt;10-hydroxy-6,11,11-tridecyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4 -3-yl]-»pyridin-2-yl-methanone OH 63⁄43⁄4 A mass spectrometry (ESI+): m/z=337 [M+H]+ 135590.doc -225 - 200927115

129 [(2 foot 6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-stupid [d]azaindole- 3-yl]-pyrimidin-4-yl-ketone OH 03⁄43⁄4 A mass spectrometry (ESI+) ·· m/z=338 [M+H]+ 130 1-{4-[(2 foot 65)-10-hydroxy-6 ,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro 4-3-carbonyl]-benzyl}-pyrrolidine -2- ketone OH A mass spectrometry (ESI+): m/z = 432 [M+H] + 131 [(2, 65)-10-hydroxy-6,11,11-tridecyl-1,2,5, 6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen+3-yl]-(4-[1,2,4]tris(sodium-1-ylmethyl-phenyl)- Methyl ketone OH A mass spectrometry (ESI+): m/z = 417 [M+H] + 132 N-{4-[(2i?, 65)-l 0-hydroxy-6,11,11-trimethyl-l ,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]azulidine-3-carbonyl]-benzyl}-acetamide OH A mass spectrometry (ESI+): m/z= 407 [M+H]+ 133 [(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-anthracene-benzene And [d]azin-3-yl]-[4-(pyrrolidin-1-carbonyl)-phenyl]-fluorenone OH 0 A mass spectrum (ESI+): m/z=433 [M+H]+ 135590 .doc 226- 200927115

134 [(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]nitrogen 4- 3-yl]-[4-(morpholin-4-carbonyl)-phenyl]-methanone OH 0 A mass spectrometry (ESI+): m/z=449 [M+H]+ 135 4-[(2 and, 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitrogen 4-3-carbonyl]- Ν-Phenyl-nodal amine OH A mass spectrometry (ESI+): m/z = 455 [M+H]+ 136 [(2/?,6,10-hydroxy-6,11,11-trimethyl-1) ,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitro-4--3-yl]-[4_(4-methyl-pyryridin-1-yl)- The phenyl]-methanone 0 compound is isolated as the trifluoroacetate salt. A mass spectrum (ESf): m/z = 462 [M+H] + 137 N-benzyl-4-[(2/?,6&lt;S&gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3-carbonyl]-benzyl Indoleamine OH 0 A mass spectrometry (ESI+): m/z = 469 [M+H]+ 138 N-ethyl-4-[(2 s 6 &lt;^-10-hydroxy-6,11,11-tridecyl) -1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine-3-carbonyl]-benzylguanamine OH 0 A mass spectrum (ESI+): m/z=407 [M+H]+ 135590.doc 227 - 200927115

139 (3H-benzimidazol-5-yl)-[(2i?,65)-6,10,11,11-tetradecyl-1,2,5,6-tetrahydro-4H-2,6- A bridge-benzo[d]azhen-3-yl]-formamidine A mass spectrometry (ESI+): m/z=374 [M+H]+ 140 (3H-benzimidazol-5-yl)-[( 2/?,6 minutes 10-fluoro-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3- Base]-fluorenone fate A mass spectrometry (ESI+) m/z = 378 [M+H]+ 141 (9-amino-6,11,11-trimethyl-1,2,5,6-tetrahydro- 411-2,6-A bridge-benzo[d]azepine-4-yl)-(3H-benzopyrimidine-s--5-yl)- formazan A mass spectrometry (ESI+): m/z=375 [ M+H]+ 142 N-ethyl-4-[(2i?,6iS)-10·ylamino-6,11,11-dimethyl-1,2,5,6-tetrahydro-4Η·2 , 6-A bridge-benzo[d]nitrogen+3_carbonyl&gt; benzinamide OH ^N\xci The compound is isolated as its trifluoroacetate salt. A mass spectrometry (ESI+): m/z = 449 [M +H]+ 143 (8,9-methylenedioxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[ d]azin-3-yl)-(3H-benzimidazol-5-yl)-methanone 1 〇c:&gt; A mass spectrum (ESI+): m/z = 404 [M+H]+ 135590. Doc 228- 200927115

144 (3-Gas-pyridin-4-yl)-[(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6 -A bridge-benzo[d] 吟-3-yl]-曱嗣?HO Cl 63⁄43⁄4 A mass spectrometry (ESI+): m/z=371/373 (Cl) [M+H]+ 145 (3H-benzene And imidazol-5-yl)-(9-fluoro-6,ll,ll-trimethyl-l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4 -3-yl)-methanone A mass spectrometry (ESI+): m/z = 378 [M+H]+ 146 (3H-benzimidazol-5-yl)-(10-methoxy-11,11 - Methyl-1,2,5,6-tetrahydro-4仏2,6-methyl bridge-benzo-azaki-3-yl)-formamidine A mass spectrometry (ESI+): m/z=376 [M+ H]+ 147 (3H-benzimidazol-5-yl)-[(2S,6i?)-9-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro -4H-2,6-methyl bridge-benzo[d]azol-4-yl]-methanone A mass spectrometry (ESI+): m/z=390 [M+H]+ 148 (3H-benzimidazole- 5-yl)-(6-phenyl-1,2,5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azepine-4-ol)-methanone starting material 6 -Phenyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine such as J. Og. (: Diaphragm 1966, 3 persons 1905-11 Obtained in the above. A mass spectrometry (ESI+): m/z = 394 [M+H]+ 135590.doc -229- 200927115 149 (3H-benzimidazol-5-yl)-(8-hydroxy-6-benzene Base-1, 2, 5, 6- Hydrogen-4H-2,6-methyl bridge-benzo[d]azepine-3-yl)-methanone starting material 6-phenyl-1,2,3,4,5,6-hexahydro-2, 6-Methyl-benzo[d]azul-8-alcohol is obtained as described in / Med CTzem. 1969, 12, 845-847. A Mass Spectrometry (ESI+): m/z = 410 [M+H] + 150 (3H-benzimidazol-5-yl)-(8-hydroxy-11,11-dimercapto-6-phenyl-1,2,5,6-tetrahydro-4H-2,6-fluorene Bridge-benzo[d]azin-3-yl)-fluorenone A mass spectrometry (ESI+): m/z = 438 [M+H]+ 151 (2, 6 Λ, 115 &gt; 3-(3Η-benzimidazole) -5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d] nitrogen 4-8-decanoic acid 0 B Mass spectrum (ES: m/z = 390 [M+H] + 152 (2i?, 6S)-3-(3H-benzimidazole-5-carbonyl)-6,ll,ll-trimethyl-1, 2,3,4,5,6-hexahydro-2,6-anthracenyl-benzo[[1]azepine-10-carboxylic acid ΗΟγΟ B mass spectrometry (ESI+): m/z=404 [M+H]+ 135590.doc 230- 200927115

153 3-(Benzothiazol-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1Η-2,6-methyl bridge-benzo[d]nitro 4-6-carboxylic acid UL&gt; 0 in OH B mass spectrometry (ESI+): m/z = 395 [M+H] + 154 3-(3H-benzimidazol-5-carbonyl)-6,11,11-trimethyl-1,2,3 ,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]nitrogen 4-9-carboxylic acid B mass spectrometry (ESI+): m/z=404 [M+H]+ 155 (2/? ,6-foot 11 benzimidazol-5-yl)-6,11-dimercapto-1,2,3,4,5,6-hexahydro-2,6-anthracene-benzo[d] nitrogen 4-8-Dimethylamine formate 0 C Mass Spectrometry (ESI+): m/z = 417 [M+H] + 156 (2i?, 6i?, 115)-3-(3H-benzimidazole-5-carbonyl )-6,11-dimercapto-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d] nitrogen -8-decanoic acid carbamide 0 amine Methane is used as a coupling partner. C mass spectrometry (ESI+): m/z = 403 [M+H]+ 157 (2/?,6/?,115)-3-(3Η-benzimidazole-5-carbonyl)-6,11-dimethyl Base-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[1] nitrogen "4-8-formamide h2n^C^JnA1〇C&gt; 0 Ammonia is used as a coupling partner. C mass spectrometry (ESI+): m/z = 389 [M+H]+ 135590.doc •231 - 200927115

158 (2 foot 6S)-3-(3H-benzimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-曱 Bridge-Benzo[(1] nitro 4-10-decanoic acid dimethyl hydrazine C mass spectrometry (ESf): m/z=431 [Μ+Ή]+ 159 (2i?,65)-3-(3H- Benzimidazole-5-carbonyl)-6,ll,ll-trimethyl-l,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d] nitrogen 4-10 - Amidyl formate uses amino methane as a coupling partner. C Mass Spectrometry (ESI+): m/z = 417 [M+H] + 160 (2 s 6β-3-(3Η-benzimidazole-5-carbonyl) )-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[(1) nitrogen 4-10-carboxamide η2ν 丫Ammonia was used as a coupling partner. C Mass Spectrometry (ESI+): m/z = 403 [M+H] + 161 3-(3Η-benzimidazole-5-carbonyl)-6,11,11-tridecyl -1,2,3,4,5,6-hexahydro-2,6-anthracene-benzo[d]nitrogen 4-9-carboxylic acid diamine C mass spectrum (ESI+): m/z = 431 [ M+H]+ 162 3-(3H-benzimidazole-5-carbonyl)-6,11,11-trimethyl-l,2,3,4,5,6-hexahydro-2,6-anthracene Bridge-stupid [d]azin-9-formic acid mesamine used as the coupling partner. C Mass Spectrometry (ESI+): m/z-417 [M+H]+ 135590.doc -232- 200927115

163 3-(311-benzimidazol-5-carbonyl)-6,11,11-tridecyl-1,2,3,4,5,6-hexahydro-2,6-anthracene-benzo[ (!) Nitrogen 4-9-formamide uses ammonia as a coupling partner. C Mass Spectrometry (ESI+): m/z=403 [M+H]+ 164 3·(Benzene °°°°-6- Slow Base····································································· (ESI+): m/z=422 [M+H]+ 165 3-(benzothiazol-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1Η-2,6-A Bridge-benzo[d]azepine-6-decanoic acid carbamide 0 Γ Aminomethane is used as a coupling partner. C Mass Spectrometry (ESI+): m/z=408 [M+H]+ 166 3-( Benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1Η-2,6-anthracene-benzo[d]nitrogen-6-6-carbamimidamine nh2 Ammonia is used as a coupling partner. C Mass Spectrometry (ESI+): m/z=394 [M+H]+ 135590.doc 233 - 200927115

167 4-[(2i?,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d] The compound of nitrogen 4-3-carbonyl]-N-methyl-N-propyl-benzylguanamine OH 0 is described in Scheme C from 4-[(2R,6S)-10-hydroxy-6,11,11 Synthesis of trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro 4-3-carbonyl]-benzoic acid and methylpropylamine. C mass spectrum (ESf): m/z = 435 [M+H] + 168 N,N-diethyl-4-[(2i?,65)-l 0-hydroxy-6,11,11-tridecyl -1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro 4-3-carbonyl]-benzylguanamine OH 0 compound as described in Procedure C, 4- [(2i?,65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]azepine- Synthesis of 3-carbonyl]-benzoic acid and methylethylamine. C Mass Spectrometry (ESf): m/z = 435 [M+H]+ 169 [(2, 65)-10-hydroxy-6,11,11-tridecyl-1,2,5,6-tetrahydro- 4H-2,6-Methyl-benzo[d]azin-3-yl]-[4-(piperidinyl)-phenyl]-carboindole 0 compound as described in Procedure C, 4 -[(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]nitrogen 4- Synthesis of 3-carbonyl]-benzoic acid and piperidine. C mass spectrometry (ESI+): m/z = 447 [M+H]+ 135590.doc 234- 200927115

170 N-benzyl-4-[(2 foot 65)-10-hydroxy-6,11,11-trimethyl-l,2,5,6-tetrahydro-4H-2,6-anthracene-benzene And [d]aza 4-3-carbonyl]-N-indenyl-nodal amine C mass spectrometry (ESI+): m/z=483 [M+H]+ 0 The compound is as described in Procedure C, 4- [(2 feet 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3 Synthesis of -carbonyl]-benzoic acid and benzylmethylamine. 171 4-[(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H_2,6·methyl bridge-benzo[d]nitrogen- 3_carbonyl]-N-propyl-benzylguanamine OH C mass spectrum (ESf): m/z = 421 [M+H] + 〇 compound as described in Procedure C, 4-[(2i?,6&gt;;S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3-carbonyl] - Synthesis of benzoic acid and n-propylamine. 172 [(2 feet 6 feet 115)-8-aminomercapto-6,11-dimercapto-1,2,5,6-tetrahydro-411-2,6-anthracene-benzoxanthene -3-yl]-(3H-benzimidazol-5-yl)-fluorenone D mass spectrum (ESf): m/z-375 [M+H]+ 173 (9-aminomercapto-6,11, 11-tridecyl-1,2,5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azul-3-yl)-(3H-benzimidazol-5-yl) -methanone nh2 D mass spectrometry (ESI+): m/z = 389 [M+H]+ 135590.doc 235 · 200927115

174 Benzothiazole-6-yl-(6-methyl-1,2,5,6-tetrahydro-4沁2,6-methyl bridge- benzo[d]azin-3-yl)-methanone E-mass spectrometry (ESI+): 111/2=349 [M+H]+ 175 3-(1Η-benzimidazol-5-carbonyl)-N-hydroxy-6,ll,ll-trimethyl-l,2, 3,4,5,6-hexahydro-2,6-indole bridge-benzo[d] nitrogen 4-9-formamidine HCk Η F mass spectrometry (ESI+): m/z=418 [M+H]+ 176 (1沁benzimidazol-5-yl)-[6,11,11-trimethyl-9-(5-mercapto-[1,2,4]oxadiazol-3-yl)-1,2 ,5,6-tetrahydro-411-2,6-methyl bridge-benzo[d]nitro-4-methyl]-methanone Η G mass spectrometry (ESI+): m/z=442 [M+H]+ 177 3-(Benzene sin*1 sitting·6·singyl)-8-yl-based-2,3,4,5-tetrachloro-1 Η-2,6-曱 bridge-benzo[d]nitrogen 4- 6-carbonitrile hX^A〇::&gt; L丨H mass spectrometry (ESI+): m/z=476 [M+H]+ 178 N-[3-(3H-benzimidazole-5-carbonyl)-6 ,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine-9-ylindenyl]-acetamide Η I mass spectrometry (ESI^: m/z = 431 [M+H] + 135590.doc 236- 200927115 179 Ν-[3-(3Η-benzimidazolecarbonyl)-6,U,ll-trimethyl-1 ,2,3,4,5,6-hexahydro-2,6-indole bridge-benzo[(!]azinium-9-yl]-6-decylamine I mass spectrometry (ESO: m/z=417 [M +H]+ 180 [(2 feet 6S>10-经基-6,11,11 - Trimethyl-1,2,5,6-tetrahydro-4Η-2,6·methyl bridge-benzo[d]azepin-3-yl]-(2-methyl-furan-3-yl)- Formazan J mass spectrometry (ESI+): m/z = 340 [M+H] + Ο 181 N-[3-(3H-benzimidazole·5-carbonyl)-6,11,11-trimethyl-1, 2,3,4,5,6-hexahydro-2,6-anthracene bridge benzo[[1]aza 4·9_yl]-methylheptin K mass spectrometry (ESI+): m/z=453 [M+H]+ ❹ 182 4-[(2/?,65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6- A bridge-benzo[d]-peptidyl]-benzoic acid OH 〇0 compound is coupled with 4-tert-butoxycarbonylbenzoic acid according to procedure A and subsequently cleaved with trifluoroacetic acid in di-methane Ester and synthetic. A mass spectrum (ESf): m/z = 380 [M+H] + 183 (3H-benzimidazol-5-yl)-(10-hydroxy-1U1-dimethyl-1,2,5,6-tetra Hydrogen-4H-2,6-indole bridge-benzo[d]azepin-3-yl)-methyl OH j? Η L mass spectrum (ESf): m/z=362 [M+H]+ 135590.doc -237- 200927115

184 [4·(2,6-Dimethyl-oxalin-4-ylindenyl)-phenyl]·[(2i?,65)-10-hydroxy-6,11,11-trimethyl·1 The 2,5,6-tetrahydro-4 fluorene-2,6-methyl bridge-benzo[d]aza 4-3-yl]methanone OH compound is isolated as its trifluoroacetate salt. A mass spectrometry (ESI+): m/z = 463 [M+H] + 185 [4-(4-carbyl-4-methyl-singe-l-yl-yl)-phenyl]-[(2 feet 65&gt;;10·hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro·4Η-2,6-methyl bridge-benzo[d]azepin-3-yl]-indanone OH ^\χα0Η The compound is isolated as its trifluoroacetate salt. A mass spectrometry (ESI+): m/z = 463 [M+H] + 186 [4-(endo-3-hydroxy-8-aza-bicyclo[ 3.2.1] Oct-8-ylmethyl)-phenyl]-[(2 and 65)-10-hydroxy-6,11,11-trimethyl-l,2,5,6-tetrahydro- 4H-2,6-A bridge-benzo[d]azepine-4-yl]-indolone oxime ά^\χσ0Η The compound is isolated as its trifluoroacetate salt. A mass spectrometry (ESI+): m/z= 475 [M+H]+ 187 [4-(3-hydroxy-.azetidin-1-ylmethyl)-phenyl]-[(2 foot 65)-10-hydroxy-6,11,11 -three The methyl-1,2,5,6-tetrahydro-4 fluorene-2,6-methyl bridge-benzo[d]aza 4-3-yl]-methanone 0H compound is isolated as its trifluoroacetate salt. A mass spectrometry (ESI+): m/z = 421 [M+H] + 188 [4-(3-hydroxypyrrolidin-1-ylmethyl)-phenyl]-[(2 s 65 &gt; 10-hydroxy- 6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-anthracenyl-benzo[d]aza- 4-3-yl]-methanone OH compound Separation of the form of trifluoroacetate. A Spectrum (ES〇: 111/2 = 435 [M + H] + 135590.doc -238- 200927115

189 [(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4- The 3-yl]-[4-(4-decyloxy-piperidin-1-ylmethyl)-phenyl]-methanone OH compound is isolated as the trifluoroacetate salt. A mass spectrum (ESI+): m/z = 463 [M+H] + 190 [4-(4-hydroxy-piperidine-1-ylmethyl)-phenyl]-[(2i^,65)-l0- Hydroxy-6,ll,ll-trimethyl-l,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]-methanone OH compound It is isolated as its trifluoroacetate salt. A mass spectrometry (ESI+): m/z = 449 [M+H]+ 191 (3H-benzimidazol-5-yl)-[(5-foot 95)-4,5,6,7,8,9-six Hydrogen-2,10,12,12-tridecyl-5,9-anthracen-1H-imidazo[5,4-j][3]benzoazepine-4-6-yl]-methanone Its trifluoroacetate form is isolated. A mass spectrometry (ESI+): m/z = 400 [M+H] + 192 [(2, 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro- 4H-2,6-anthracenyl-benzo[d]azepin-3-yl]-(lH-oxime. sit-3-yl)-曱嗣0H A mass spectrum (ESI+): m/z=376 [M +H]+ 193 (5-fluoro-1Η-indol-3-yl)-[(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetra Hydrogen-4Η-2,6-methyl bridge-benzo[d]azin-4-yl]-methanone 0H A mass spectrum (ESP): m/z=393 [M+H]+ 135590.doc -239- 200927115

194 [(2Λ,65&gt; 10-carbyl-6,1U1-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine-3- ]]-(1-methyl-S--3-yl)-曱嗣ΟΗ A mass spectrometry (ESI+): m/z=390 [M+H]+ 195 [(2 s 65)· 10-hydroxy-6,11 ,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitro 4-3-yl]-(4-methoxy-1Η-σ5 |〇丁-3-基)_曱嗣ΟΗ 〇/ 03⁄4令 A mass spectrum (ESf): m/z=405 [M+H]+ 196 (5-gas-1Η-吲哚-3-yl)-[ (2 feet 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-曱 bridge-benzo[d]nitrogen 4-3- ]-OH ketone OH JA mass spectrometry (ESI+): m/z=409/411 (Cl) [M+H]+ 197 [(2/?,65)-10-hydroxy-6,11,11 -3曱1,2-,5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azepine-4-ol]-(2-mercapto-1H-indol-3-yl) -Mettone feNlxp A mass spectrometry (ESI+): m/z = 389 [M+H]+ 198 benzofuran-3-yl-[(2 foot 65)-10-hydroxy-6,11,11-trimethyl -1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azin-3-yl]-oxime OH A mass spectrometry (ES〇: m/z=376 [M +H]+ 135590.doc -240- 200927115

199 [(2i?,65&gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine- 3-yl]-(l-fluorenyl-1H-indol-3-yl)-fluorenone A mass spectrometry (ESI+): m/z=389 (CI) [M+H]+ 200 (3H-benzo[alpha] m 0 sits -5-yl)-(6-ethyl-8-carbyl-11-methyl-l,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d] Nitro 4-3-yl)-fluorenone oxime The 1Cd compound is a racemic mixture of the indicated diastereomers. A Mass Spectrum (ESI+): m/z = 390 [M+H] + 201 (2i? ,6&gt;S)-3-(3H-benzimidazole-5-carbonyl)-6,ll,ll-trimethyl-l,2,3,4,5,6-hexahydro-2,6-A Bridge-benzo[d]nitrogen 4-8-prosthetic diamine Λ field 1α:; 0 A mass spectrum (ESI+): m/z=467 [M+H]+ 202 (2 feet 65)-3 - (3Η-stupidimide-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[{1] Nitrogen 4-8-supply acid decylamine 0 A mass spectrometry (ESI+): m/z = 453 [M+H]+ 203 (2 s. 65) -3-(3 Η-benzimidazole-5-carbonyl)-6 ,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d] atmosphere °^-8_continued amine h2n^XX^jnAqc ) 0 A mass spectrum (ESI+): m/z = 439 [M+H]+ 135590.doc -241 - 200927115

204 l-[(2i?,65)-3-(3H-Bumimidazole-5-carbonyl)-6,l 1 ,11-trimethyl-1 ,2,3,4,5,6-hexahydro -2,6-methyl bridge-benzo[d]azinyl]-ethanone 0 A mass spectrum (ESf): m/z=402 [M+H]+ 205 1-[(2Λ,65&gt;3-( 3Η-benzimidazole-5-carbonyl)·6,11,11-trimethyl-1,2,3,4,5,6-hexa-argon-2,6-methyl bridge-benzo[d]azepine -9-yl]-ethanone A mass spectrometry (ESI+): m/z-402 [M+H]+ 206 (2i?, 65)-3-(3H-benzoimidazole-5-carbonyl)-6,ll , ll-trimethyl-l,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[cl]azin-9-carbonitrile NWa:; A mass spectrometry (ESI+): m/z=385 [M+H]+ 207 4-[(2/?,6S)-4-G〇-hydroxy-6,ll,n-trimethyl-1,2,5,6-tetrahydro -4H-2,6-A bridge-benzo[d]qisaki-3-carbonyl)-]]-morpholine-3-one OH 〇^νΛ〇Χ? A mass spectrometer ^siV m/z=449 [ M+H]+ coupling conjugate 4-(3-oxo-morpholin-4-ylmethyl)-benzoic acid is NaH from 3-sided oxy-morpholine and 4·bromomethylbenzoic acid The base and hydrazine were used as a solvent, followed by hydrolysis with KOH in MeOH. 208 44(2/^,6^10-hydroxy-6,11,11·trisyl-1,2,5,6-tetrazole-4H-2,6-anthracene-benzo[d]|t4 -3-carbonyl]-N-indenyl-N-phenyl-benzylguanamine A mass spectrometry (ESI+): m/z = 469 [M+H]+ 々AD 135590.doc -242- 200927115

209 (3H-Benzamidazol-5-yl)-[(2i?,65)-9-(l-hydroxy-ethyl)-6,11,11-trimethyl-1,2,5,6- Tetrahydro-4H-2,6-anthracenyl-benzo[d]azol-4-yl]-methanone OH Μ mass spectrometry (ESI+): m/z=404 [M+H]+ 210 [(2 feet) 6^)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen&lt;4-3- ]]-(6-Mercapto-3H-benzimidazol-5-yl)-fluorenone OH A mass spectrum (ESI+): m/z=390 [M+H]+ 211 (3H-benzimidazole-5- Base)-[(2 foot 65)-8-(1-hydroxy-ethyl)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge -Benzo[d]azepin-3-yl]-fluorenone OH Μ mass spectrometry (ESI+): m/z = 404 [M+H] + 212 3-(3H-benzimidazole-5-carbonyl)-8 -hydroxy-2,3,4,5-tetrahydro-1Η-2,6-methyl bridge-benzo[d]gas+6-formic acid vinegar 〇Χ〇Χ%ν1Ό:) 〆人0〆A mass spectrometry (ESI+ ): m/z=392 [M+H]+ 213 3-(3Η-benzimidazole-5-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1Η-2,6-A Bridge-benzo[d]nitrogen 4-6-carboxylic acid 0 human OH 质谱 mass spectrum 0ESI+): m/z=378 [M+H]+ 214 3-(3H-benzimidazole-5-carbonyl)-8-hydroxyl -2,3,4,5-tetrahydro-1H-2,6-anthracenyl-benzo[d]nitrogen 4-6-carboxamide quinone nh2 A mass spectrometry (ESI+): m/z=377 [M +H]+ 135590.doc -243 - 200927115

215 (2,5-Dimethyl-2-oxapyrazol-3-yl)-[(2 foot 65)-10-hydroxy-6,11,11-tridecyl-1,2,5,6-tetra Hydrogen-4H-2,6-methyl bridge-benzo[d]azol-4-yl]-methanone OH A mass spectrometry (ESI+): m/z=354 [M+H]+ 216 [(2 feet 65&gt;; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azepine-4-ol]-(2) -phenyl-2H-pyrazol-3-yl)-methanone OH A mass spectrometry (ESI+): m/z = 402 [M+H]+ 217 benzo[b]thiophen-3-yl-[(2) 65&gt;10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge·benzo[d]nitro 4-3-yl]-oxime Ketone OH 03⁄43⁄4 A mass spectrometry (ESI+): m/z = 392 [M+H]+ 218 [(2, 65)-10-hydroxy-6,11,11-tridecyl-1,2,5,6- Tetrahydro-4H-2,6-anthracenyl-benzo[d]azepine-4-yl]-(3-phenyl-3H-imidazol-4-yl)-methanone OH 03⁄41⁄2 A mass spectrometry (ESI+): m/z=402 [M+H]+ 219 [(2^65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6- Anthracycline-benzo[d]azepine-4-yl]-(4,5,6,7-tetrahydro-111-oxazol-3-yl)-fluorenone OH A mass spectrometry (ESI+): m/z =380 [M+H]+ 135590.doc -244- 200927115

220 [(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]azepine- 3-yl]-(1,4,5,6-tetrahydro-cyclopentazol-3-yl)-fluorenone OH A mass spectrum (ESI+): m/z = 366 [M+H]+ 221 [ (2/?,65&gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine-3 -(5-phenyl-2H-pyrazol-3-yl)-methanone OH 03⁄43⁄4 A mass spectrum (ESI+): m/z=402 [M+H]+ 222 (1 -ethyl-1H- Indole-3-yl)-[(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzene And [d]azacrid-3-yl]-methanone OH ' 〇A mass spectrometry (ESI+): m/z=403 [M+H]+ 223 (2/?,6i?,115&gt;3-(3H- Benzimidazole-5-carbonyl)-8-hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine -9-carbonitrile A mass spectrometry (ESI+): m/z = 387 [M+H]+ 224 (311-benzimidazol-5-yl)-[(6 ft. 10 s. 125) _ 5,6,7, 8,9,10-hexahydro-10,12-dimercapto-6,10-anthracene-1H-imidazo[5,4-i][3]benzoazepin-7-yl]-anthone Excitation WA mass spectrometry (ESr): m/z=386 [M+H]+ 135590.doc 245 - 200927115

225 [(2 feet 65 &gt; 10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetraar-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3 -yl]-(7-methyl-1H-benzimidazol-5-yl)-methanone OH VA mass spectrometry (ESI+): m/z=390 [M+H]+ 226 3-(3H-benzo Imidazole-5-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1Η-2,6-fluorene bridge-benzo[d]nitrogen 4-6-indolecarbonitrile 'J Η mass spectrometry (ESI+) : m/z = 359 [M+H]+ 227 (2 feet 6 feet 115&gt; 3-(3H-benzimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4, 5,6-Hexahydro-2,6-anthracene-benzoxanthene-9-indoleonitrile A mass spectrometry (ESI+): m/z=387 [M+H]+ 228 (2 feet 6iU15)-(3H -benzimidazol-5-yl)-[6,11-dimethyl-8-(1Η-tetrazol-5-yl)-1,2,5,6-tetrahydro-4H-2,6-oxime Bridge-benzo[d]azhen-3-yl]-methanone Vn 质谱 mass spectrometry (ESI+): m/z=414 [M+H] s 229 (3H-benzimidazol-5-yl)-[( 2/?,65)-8-(l-hydroxy-1-methyl-ethyl)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6- A bridge-benzo[d]azol-4-yl]-fluorenone OH 0 mass spectrometry (ESI+): m/z=418 [M+H]+ 135590.doc 246- 200927115

230 (2i?,6i?,115)-3-(3H-benzimidazole-5-carbonyl)-N-hydroxy-6,11-dimercapto-1,2,3,4,5,6-six Hydrogen-2,6-methyl bridge-benzo[d]nitrogen 4-8-formamidine h2NtX)^jnA〇:} h〇-n F mass spectrometry (ESI+): m/z=404 [M+H]+ 231 (3H-benzimidazol-5-yl)-[(2i?,6i?,115&gt;6,11-dimercapto-8-(5-fluorenyl-[1,2,4]oxadiazole-3 -yl)-l,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]azol-4-yl]-methanone-NG mass spectrometry (ESI+): m/z =428 [M+H]+ 232 (3H-benzimidazol-5-yl)-[(2 and, 6-foot 115)-6,11-dimethyl-8-[1,2,4] Zyrid-3-yl-1,2,5,6-tetrahydro-4H-2,6-indole bridge-benzo[d]azin-3-yl]-indolone oxime-NP mass spectrometry (ESI+): m /z=414 [M+H]+ 233 (3H-benzimidazol-5-yl)-[(2 foot 65)-8-nonanesulfonyl-6,11,11-trimethyl-1, 2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azac-3-yl)-methanone 0 A mass spectrum (ES: m/z = 438 [M+H] + 234 (3H-benzimidazol-5-yl)-[(2 foot 65)-10-methanesulfonic acid-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H -2,6-A bridge-benzo[[1]-3--3-)-methyl 〇γ〇〇A mass spectrometry (ESI+): m/z=438 [M+H]+ 135590.doc 247- 200927115

235 (3H-benzimidazol-5-yl)-[(7/?,115&gt; 6,7,8,9,10,11-hexahydro-11,13,13-tridecyl-6,10-甲桥』比嗪和[2,3-i] [3]benzoazepin-8-yl]-methanone A mass spectrometry (ESI+): m/z=412 [M+H]+ 236 (2 feet 6i ?,ll/?)-3-(3H-benzimidazole-5-carbonyl)-6,11-dimercapto-1,2,3,4,5,6,8,9-human hydrogen-2, 6-曱 bridge-benzo[d]azepine-9-indoleonitrile A mass spectrometry (ESI+): m/z=371 [M+H]+ 237 (2/?,65)-3-(3H-benzo Imidazole-5-carbonyl)-6,ll,ll-trimethyl-l,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d] nitrogen 4-9-continued Amantadine A mass spectrometry (ESI+): m/z = 467 [M+H]+ 238 (3H-benzimidazol-5-yl)-[(6-foot 105)-5,6,7,8, 9,10-hexahydro-2,10,12,12-tetramethyl-6,10-anthracen-1 imidazo[5,4-i][3]benzoaze-7-yl]- Anthrone A mass spectrometry (ESI+): m/z = 414 [M+H] + 239 (3H-benzimidazol-5-yl)-[(67?, 105&gt;5,6,7,8,9,10 -Hexahydro-10,12,12-trimethyl-6,10-methyl bridge-1H-imidazo[5,4-i][3]benzoazepin-7-yl]-methanone 1α: A Mass Spectrometry (ESr): m/z=400 [M+H]+ 135590.doc 248- 200927115

240 (3H-benzimidazol-5-yl)-[(6/U〇-5,6,7,8,9,l〇_hexahydro-3,10,12,12-tetradecyl-6 , l〇-methyl bridge-imidazo[4,5·ί][3]benzoazepine-7-7-yl]-methanone. A mixture of Example L was used as a starting material; the compound was obtained by reverse phase HPLC Separated from compound example 241. A mass spectrum (ESI+): m/z = 414 [M+H] + 241 (3H·benzimidazol-5-yl)-[(6/?,1〇5,6,7 ,8,9,1〇-hexahydro-1,1〇,12,12-tetradecyl-6,10-methyl bridge-imiphtho[5,4-i][3]benzoazepine-7 -Based--methanone. A mixture of Example L was used as the starting material; this compound was separated from compound Example 24 by reverse phase HPLC. A mass spectrum sr): m/z = 414 [M+H]+ 242 (3H-benzimidazol-5-yl)-[(6-foot 10, 5,6,7,8,9,10-hexanitro-1,2,10,12,12-pentamethylene-6,10 - A bridge-Miso sitting and [5,4-i][3]benzoazepin-7-yl]-fluorenone A mass spectrometry (ESI+): m/z=428 [M+H]+ 243 (3H -benzimidazole _5_yl)-[(6/i, i0S&gt;5,6,7,8,9,10-hexanitro-2,3,10,12,12-pentamethylene-6,10-甲桥-ο米〇 sit and [4,5-i][3]benzoazide _7_yl]-methylamine A mass spectrometer (ESI+): m/z=428 [M+H]+ 244 (3H -benzimidazole-5-yl)-[(7 , 11 sentences_ 6,7,8,9,10,11-hexahydro-2,3,11,13,13-pentamethyl-7,11-methyl bridge-pyrazine[2,3-i] [3] Benzodiazepine 4-8-yl]- ketone A mass spectrometry (ESf): m/z = 440 [M+H]+ 135590.doc -249· 200927115

245 (3H-benzimidazol-5-yl)-(2,3,4,5,6,7-hexahydro-2,6-methyl bridge-nitro-[5,4-b]indole-3 -yl)-methanone^Νΐα&gt; A mass spectrum (ESI+): m/z = 357 [M+H]+ 246 (3Η-benzimidazol-5-yl)-[(2&amp;65; 115)-8- Hydroxy-6,11-dimethyl-1,2,5,6·tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitro 4-3-yl)-methanone A mass spectrometry (ESI+) : m/z=362 [M+H]+ 247 (3H-benzimidazol-5-yl)-[(2i^,6/^,lli^)-8-hydroxy-6,ll-didecyl- l,2,5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d] gastrien-3-yl)-formamidine A mass spectrometry (ESI+): m/z=362 [M+H ]+ 248 [(2/?,65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d] ]N- 4-3-yl)-(5-fluorenyl-1H-indol-3-yl)-fluorenone OH / Η A mass spectrometry (ESI+): m/z = 389 [M+H]+ 249 (3Η -benzimidazol-5-yl)-[(2 foot 6 ft 115)-6,11-dimercapto-8-phenyl-1,2,5,6-tetrahydro-4 private 2,6-anthracene Bridge-benzo[d]aza 4-3-yl)-fluorenone A mass spectrometry (ESI+): m/z=422 [M+H]+ 135590.doc 250- 200927115

250 (3H-benzimidazol-5-yl)-[(2 foot 6-foot 115)-6,11-dimethyl-8-. Bipyridine-3-yl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl]-methanone A mass spectrometry (ESP): m/ z=423 [M+H]+ 251 (3H-benzimidazol-5-yl)-[(2i?,6i?,l 15)-6,11-dimethyl-8-acridin-4-yl -1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azol-4-yl]-methanone A mass spectrometry (ESI+): m/z = 423 [M+ H]+ 252 (3H-benzimidazol-5-yl)-[(2/?,6-foot 115)-6,11-dimethyl-8-pyrimidin-5-yl-1,2,5,6 -tetrahydro-4H-2,6-methyl bridge-benzo[d]azol-4-yl]-methanone A mass spectrometry (ESf): m/z = 424 [M+H]+ 253 (3H-benzene And imidazol-5-yl)-(4,6-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepin-3-yl)- Racemic mixture of the enantiomers of the fluorenone A mass spectrum (ESI+): m/z = 346 [M+H]+ 254 (3H-benzimidazol-5-yl)-[(7 foot 115&gt;; 6,7,8,9,10,ll·hexahydro-3,ll,13,13-tetramethyl-7,ll-曱 bridgerazine[2,3-i][3]benzonezepine +8-yl]-methanone This compound was obtained as a mixture with Compound Example 255. A mass spectrum (ESI+): m/z=426 [M+H]+ 135590.doc •251 - 200927115 255 6 7 Taste bite 5-base)-[(7 and, 115&gt; "=,9,10,11-hexahydro-2,11,13,13-tetra Base-7,11-methyl bridge is more than [2,3-i][3]benzoazepin-8-yl]-methanone. This compound is obtained as a mixture with compound example 254. (ESf): m/z = 426 [M+H] + 256 (1. mercapto-1H-indol-3-yl) 4(2^65^-6,11,11-trimethyl-1, 2,5,6-tetrahydro·4Η-2,6-methyl bridge-benzo[d]azul-3-yl]•曱嗣A mass spectrometry (ESI+): m/z=373 [M+H]+ 257 (3H:benzimidazol-5-yl)-[(6-foot 10S)-5,6,7,8,9,10-hexahydro-l,l〇,12,12-tetradecyl-6, l〇-A bridge-triazolo[5,4_i][3]benzoazepine 4_7-yl]-fluorenone A mass spectrometry (ESf): m/z=415 [M+H]+ The mixture of Example 258 was obtained by separation of 258 (3H-benzimidazol-5-yl)-[(6 and,1〇5)-5,6,7,8,9,10- by palm phase HPLC. Hexahydro-3,10,12,12-tetramethyl-6,10-methyl bridge-triazolo[4,5-i][3]benzoazepin-7-yl]-methanone&lt;^ ΝΧα:&gt; This compound was obtained as a mixture with Compound Example 257, which was separated by HPLC on the palm phase A mass spectrometry (ESI+): m/z = 415 [M+H] + 259 (1 Η-吲哚-3 -基)-[(2 foot 65&gt;6,11,11-tridecyl-1,2,5,6-tetrahydro-criminal-2,6-quinone-benzene And [(1)N 4-3-yl]-曱嗣 Η A mass spectrum (ESf): m/z=359 [M+H]+ 135590.doc -252- 200927115 ❹

260 [(2 foot 65)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]azepine- 3-yl]-[3-(2,2,2-trifluoro-1-yl-1-methyl-ethyl)-phenyl]-methanone?Η 0 OH A mass spectrum (ESf): m/ z=448 [M+H]+ 261 (3H-benzimidazol-5-yl)-[(2i?,6i?,llS)-8-methoxy-6,11-dimethyl-7-nitrate Base-1,2,5,6-four winds J-4H· 2,6-methyl bridge-benzo[d]azepin-3-yl]-fluorenone. 〆'〆A mass spectrometry (ESI+): m/z=421 [M+H]+ 262 (3Η-benzimidazol-5-yl)-[(2 足6足11 &gt;S)-6,11 - Dimethyl-8-(2-methyl-pyrimidin-4-yl)-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]azepine-4-yl ]-methanone N丫NA mass spectrometry (ESI+): m/z = 438 [M+H]+ 263 (3H-benzimidazol-5-yl)-[(2 foot 6i?, 115)-6,ll- Dimethyl-8·(6-methyl-d-heptyl-3-yl)-1,2,5,6-four wind·4Η-2,6-曱 bridge-benzo[d]nitrogen 4-3 -yl]-methanone A mass spectrometry (ESI+): m/z = 438 [M+H]+ 264 (3H-benzimidazol-5-yl)-[(2, 6 and 115)-6,11 - Mercapto-8-°3⁄40定-4·yl-1,2,5,6-tetrazol-4Η·2,6-methyl bridge-benzo[d]aza 4-3-yl]-methanone N^ NA mass spectrum (ESI+): m/z = 424 [M+H]+ 135590.doc -253 - 200927115

265 (3H-benzimidazol-5-yl)-[(6-foot 1 〇5)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10 -A bridge-1 沁 triazolo[5,4-i][3]benzoazepin-7-yl]-fluorenone excitation 1 A mass spectrometry (ESI+): m/z=401 [M+H]+ 266 (3H-benzimidazol-5-yl)-[(6i?,105)-5,6,7,8,9,10-hexahydro-10,12,12-tridecyl-2-» ratio Pyrazin-2-yl-6,10-methyl bridge-isoxazolo[5,4-i][3]benzoazepin-7-yl]-methanone A mass spectrometry (ESI+): m/z=478 [ M+H]+ 267 (3H-benzoxazol-5-yl)-[(2 foot 6 ft 115)-7-amino-8-methoxy-6,11-dimercapto-1,2 , 5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azepin-3-yl]-fluorenone.勒νη2 Q mass spectrometry (ESI+): m/z=391 [M+H]+ 268 N-[(2i?,6i?,115)-3-(3H-benzimidazole-5-carbonyl)-8-A Oxy-6,11-dimercapto-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]azepine-7-yl]-methanesulfonamide r° κ mass spectrometry (ESI+): m/z = 469 [M+H]+ 269 [(6 s. 105)-2-(1 - ethinyl-piperidin-4-yl)-5,6,7, 8,9,10-hexahydro-10,12,12-trimethylphenyl-6,10-methyl bridge-sazo[5,4-i][3]benzoazepine-7-7-yl]-( 3H-benzimidazol-5-yl)-methanone V A mass spectrometry (ESI+): m/z = 525 [M+H]+ 135590.doc 254- 200927115

❹ 270 (3沁benzimidazol-5-yl)-[(2 foot 6-foot 115)-8-methoxy-6,11-dimethyl·7·α-pilot-1-yl-1,2 ,5,6-tetrazol-4Η-2,6·曱 bridge·benzo[d]nitro 4-3-yl)-fluorenone ύ R mass spectrometry (ESI+): m/z=441 [M+H]+ 271 (3Η-benzimidazol-5-yl)-[(6-foot 105)-2-cyclopropyl-5,6,7,8,9,10-hexahydro-10,12,12-tridecyl -6,10-曱 bridge-N-zoledo[5,4-i] [3] benzoazepine-4-7-yl]-methanone A mass spectrometry (ESI+): m/z=440 [M+H]+ 272 (3H-benzimidazol-5-yl)-[(6-foot 105)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(1- Methyl-6-o-oxy-1,6-dihydro-pyridin-3-yl)-6,10-indole bridge-isoxazo[5,4-i][3]benzazepine-7- Methyl ketone A mass spectrometry (ESI+): m/z = 507 [M+H]+ 273 (3H-benzimidazol-5-yl)-[(6/?,105)-2-tert-butyl -5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methyl bridge-isoxazolo[5,4-i][3] -7-yl]-fluorenone A mass spectrometry (ESI+): m/z = 456 [M+H]+ 274 (3H-benzimidazol-5-yl)-[(6 11 hexahydro-10,12, 12-trimethyl-2-» butyl-3-yl-6,10-methyl bridge-isoxazolo[5,4-i][3]benzoazepine-7-7-yl]-methanone A mass spectrometry (ESI+): m/z=477 [M+H]+ 135590.doc 255 - 200927115

275 (3H-benzimidazol-5-yl)-[(6i?,105)-5,6,7,8,9,10-hexanitro-10,12,12-dimethyl-2-[( S}-tetrazol-Of-but-2-yl]-6,10-methyl-bromotetrazolo[5,4-i][3]benzoazepine-7-7-yl]-methanone A mass spectrometry (ESI+) : m/z=470 [M+H]+ 276 (3H-benzimidazol-5-yl H(6i^,105)-5,6,7,8,9,10-hexahydro-10,12, 12-trimethyl-2-pyridazin-4-yl-6,10-methyl bridge-imidazo[5,4-i][3]benzoazepine-7-7-yl]-fluorenone compound F3co2h salt form separation A mass spectrometry (ESI+): m/z=478 [M+H]+ 277 (3H-benzimidazol-5-yl)-[(6 brothers 105)-5,6,7,8,9 ,10-hexahydro-10,12,12-trimethyl-2-(5-methyl-pyridyl-heptyl-2-yl)-6,10-anthracene-isoxazo[5,4-i] [3] Benzoazin 4-7-yl]-methanone tune:: &gt; A mass spectrometry (ESI+): m/z = 492 [M+H]+ 278 quinoxaline-6-yl-[( 2 feet 65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracenyl-bromo-[d]azin-3-yl]-methanone A mass spectrum (ES^): m/z-372 [M+H]+ 279 (3H-benzimidazol-5-yl)-[(2 foot 6 foot 115)-6,11-didecyl-8- (1-mercapto-2-epoxy-1,2-diode·0 to -4-yl)·1,2,5,6·tetrahydro-4Η-2,6·曱 bridge·benzo [d]N- 4-3-yl]-methanone 9 A mass spectrometry (ESI+): 0 m/z = 453 [M+H]+ 13559 0.doc 256- 200927115

280 (4-Nitro-phenyl)-[(2 foot 65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4仏2,6-anthracene-benzo [(1)azepin-3-yl]•曱嗣1 _ 〇A mass spectrometry (ESI+): m/z=365 [M+H]+ 281 (4-amino-2,3,5,6-four Fluorine-phenyl ΗαΛ, όβ-ό, 11,11-trimethyl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]nitro 4-3-yl] -fluorenone FA mass spectrometry (ESI+): m/z = 407 [M+Hf 282 naphthalen-2-yl-[(2i?, 65)-6,ll,ll-trimethyl-1,2,5,6 -tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen &lt;4-3-yl]-fluorenone A mass spectrometry (ESI+): m/z=370 [M+H]+ 283 (4 -amino-3,5-diqi-phenyl)-[(2 foot 65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-A Bridge-benzo[d]azepin-3-yl]-fluorenone Cl A mass spectrometry (ESD: m/z=403/405/407 (2C1) [M+H]+ 284 naphthalene-1 -yl-[( 2 Foot 65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine-4-ol]-methanone A mass spectrometry (ESI+): m/z = 370 [M+H]+ 285 (1H-carbazol-6-yl)-[(2, 65)-6,11,11-tridecyl-l,2, 5,6-Tetrahydro-4H-2,6-anthracene-benzo[d]azin-3-yl]-methanone A mass spectrometry (ESI+): m/z=360 [M+H]+ 135590. Doc •257- 200927115

286 (4-Amino-phenyl)-[(2 brother 65)-6,11,11-tridecyl 1,2,5,6-tetrahydro-4H-2,6-methyl bridge benzo[ d] Nitrogen "4-3-yl]-fluorenone A mass spectrometry (ESI+): m/z = 335 [M+H] + 287 (3H-benzimidazol-5-yl)-[(6/?, 105&gt ;5,6,7,8,9,1 Ο-α St10,12,12-dimethyl-2-[(i?)-tetrazol0f0nan-2-yl]-6,10-A Bridge-to-azolo[5,4-i][3]benzoxazine+7-yl]-fluorenone A mass spectrometry (ESI+): m/z=470 [M+H]+ 288 6-[(2i? ,6S&gt;6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen+3-carbonyl)-indoline-1 -ketone A mass spectrometry (ESI+): m/z = 374 [M+H]+ 289 5-[(2 foot 6 foot 115)-3-(3沁benzimidazole-5-carbonyl)-6,11-di Methyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge-benzo[d]nitrogen 4-8-yl]-bumethyl-1Η-»bipyridine-2-one oxime A mass spectrometry (ESI+): m/z = 453 [M+H]+ 290 6- [(2,6,6,1,1,1,3,3,3 - (3H-benzimidazol-5-carbonyl)-6,11-dimethyl- 1,2,3,4,5,6-hexahydro-2,6-indole bridge-benzo[d]nitro 4-8-yl]-2-methyl-2H-pyridazin-3-one human N 1 A mass spectrometry (ESI+): m/z = 454 [M+H]+ 291 (3-hydroxy-dihydroindol-5-yl)-[(2i?,65)-6,11,11-trimethyl -1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro 4-3-yl]-methanone M mass spectrometry (ESf) : m/z=376 [M+H]+ 135590.doc -258- 200927115

292 (3-carbyl-3-methyl-dioxin Ip-5-yl 11, 11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge_benzo[ d]aza 4-3-yl]-methanone 八八9, OH 〇^νΛ〇5 0 mass spectrometry (ESI+): m/z=390 [M+H]+ 293 (1H-called h sat-5-based )-[(2/?,65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3 -yl]-methanone A mass spectrometry (ESI+): m/z = 360 [M+H]+ 294 (3Η-benzimidazol-5-yl)-(5,6-dimethyl-1,2, 5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d]azol-4-yl)-methanone (racemic mixture of diastereomers shown) A mass spectrometry (ESI+ ): m/z = 346 [M+H] + 295 (4-amino-3-carbophenyl)-[(2/?,65&gt;6,11,11-trimethyl-l,2, 5,6-tetrahydro-4H-2,6-anthracenyl-benzo[d]azepine-4-phenyl]-fluorenone A mass spectrometry (ESI+): m/z=369/371 (Cl) [M+ H]+ 296 (4-amino-3-fluoro-phenyl)-[(2 foot 65)-6,ll,ll-trimethyl-1,2,5,6-tetrahydro-4H-2, 6-曱 bridge-benzo[d]azepin-3-yl]•曱嗣A mass spectrometry (ESI+): m/z=353 [M+H]+ 297 (3,4,5-tris-phenyl )-[(2 foot 65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitro 4-3-yl ]-methanone FA mass spectrometry (ESI+): m/z=374 [M+H]+ 135590.doc -259 - 200927115

298 5- [(2Λ,65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen 4-3- Carbonyl]-1,3-diar-indol-2-one Q^n1o&gt;. Η A mass spectrometry (ESI+): m/z=375 [M+H]+ 299 1 - {4-([(2) 65)-6,11,11-tridecyl-1,2,5,6- Tetrahydro-4Η-2,6-anthracenyl-benzo[d]nitro 4-3-carbonyl]-phenylacetophenone A mass spectrometry (ESI+): m/z=362 [M+H]+ 300 (3H -benzimidazol-5-yl)-[(7-foot 11-foot 125&gt; 6,7,8,9,10,11-hexahydro-2,11,12-trimethyl-6,10-anthracene bridge- Oxazolo[4,5-h][3]benzone4-8-yl]-fluorenone A mass spectrometry (ESI+): m/z=401 [M+H]+ 301 (3H-benzimidazole- 5-yl)-[(6/?,105)-5,6,7,8,9,10-hexahydro-2,10,12,12-tetramethyl-6,10-anthracene-oxazole And [4,5-i][3]benzazepine-7-yl]-methanone A mass spectrometry (ESI+): m/z=415 [M+H]+ 302 (3H·benzimidazole-5- Base)-[(6-foot 105)-2-cyclopropyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methyl bridge-oxazole And [4,5-i] [3]benzoazepine-4-7-yl]-fluorenone A mass spectrometry (ESI+): m/z-441 [M+H]+ 303 (6-hydroxy-pyridine-3- Base)-[(2/?,65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo[d]azepine 3-yl)-methanone A mass spectrometry (ESI+): m/z=337 [M+H]+ 135590.doc •260- 200927115

304 (6-Amino-pyridin-3-yl)-[(2ii,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene bridge _Benzo[d]azin-3-yl)-fluorenone A mass spectrometry (ESI+): m/z=336 [M+H]+ 305 (3Η-benzimidazol-5-yl)-[(6 feet) 10 feet 125)-5,6,7,8,9,10-hexahydro-2,10,12-trimethyl-6,10-methyl bridge-oxazolo[5,4-i] [3] Benzoazin-7-yl]-methanone A mass spectrometry 〇ESI+): m/z=401 [M+H]+ 306 [4-(1-hydroxy-1-methyl-ethyl)-phenylhydrazine ,όβ-ό, 11 , 11 -trimethyl-1,2,5,6-tetrahydro-4H-2,6-indole-benzo[d]azaki-3-yl]-fluorenone 0 mass spectrometry (ESI+): m/z=378 [M+H]+ 307 1 - {3 -[(2 foot 65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4Η -2,6-曱 bridge-benzo[d]nitro 4-3-carbonyl]-phenyl}·ethanone A mass spectrum (ESf): m/z=362 [M+H]+ 308 3,3- Mercapto-5-[(2i?,65&gt;6,l 1,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azepine -3-yl]-1,3-diaza-. 引出-2-嗣Η A mass spectrometry (ESI+): m/z=403 [M+H]+ 309 (1 Η-benzimidazole-5- (6,11,11-trimethyl-7-acridin-3-yl-1,2,5,6-tetrahydro-4Η-2,6-methyl bridge-benzo[d] 吟· 3-Base)-曱嗣ό Η A mass spectrometry (ESI+): m/z=437 [M+H]+ 135590. Doc -261 - 200927115 ❹ Ο 310 [3-( 1 -Phenyl-ethyl)-phenyl]-[(2Λ,65)-6,11,11 -trimethyl-1,2,5,6· Tetrahydro-4Η-2,6-methyl bridge-stupid μ] gas-based]-fluorenone oxime mass spectrometry (Esr): m/z=364 [M+H]+ 311 (3H-benzopyrazine-5- Base)-[(6 feet 10 see 12] 2-cyclopropyl-5,6,7,8,9,10-hexa-argon-l〇,12-dimethyl-6,l〇-甲桥-恶Azolo[5,4-i][3]benzazepine 4-7-yl]-methanone η collapse V》 A ^------ mass spectrum (ESI+): m/z=427 [M+H ]+ 312 (3Η-benzimidazol-5-yl)-[(6/?,105)-2-tert-butyl-5,6,7,8,9,10-hexahydro-10,12, 12-tridecyl·6,1 〇-methyl bridge-oxazole[4,5_i][3]benzoazepine-7-7-yl]-fluorenone A mass spectrometry (ESf): m/z=457 [M +H]+ 313 ------------- . - --' (3Η-benzimidazol-5-yl)-[(6 and,105)-5,6,7,8 ,9,10-hexahydro-10,12,12-trimethyl-2-(5-methyl-»b-2-yl)-6,10-methyl bridge-oxazole[4,5- i][3]benzoazepin-7-yl]-methanone A mass spectrum (ESr): m/z = 493 [M+H]+ 314 [3-(1-hydroxy-ethyl)-phenyl] -[(2 尺 65)-6,11,11-彡methyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen °^·-3- Base]-曱嗣Q^V Μ mass spectrometry (ESI+): m/z=364 [M+H]+ 315 (3Η-benzimidazole-5 -yl)-[(2Λ,6/?,115&gt;6,11-dimethyl-8-(2-methylpyrimidin-5-yl)-1,2,5,6-tetrahydro-4Η- 2,6-A bridge-benzo[d]azepin-3-yl]-fluorenone AL·——^ Mass spectrometry (ESI+): m/z=438 [M+H]+ 135590.doc -262- 200927115 Ο

316 3-(1Η-benzimidazole-5-carbonyl)-6,11,11-tridecyl-1,2,3,4,5,6-hexahydro-2,6-methyl bridge·benzo[ d]azepine·7·phthalonitrile L丨Η A mass spectrometry (ESI+): m/z=437 [M+H]+ 317 [3-(1-yl-1-yl-ethyl)-phenyl ]-[(2i?,65&gt;6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-anthracene-benzo-argon&gt; 4-3-yl ]-methanone 0 mass spectrometry (ESI&quot;): m/z = 378 [M+H]+ 318 (4-hydroxy-phenyl)-[(2 foot 65)-6,11,11-trimethyl·1 ,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]azin-3-yl]-methanone A mass spectrometry (ESI+): m/z=336 [M+H] + 319 (3-hydroxy-phenyl)-[(2/?,65)-6,11,11-trimethyl-l,2,5,6-tetrahydro-4Η-2,6-曱 bridge- Benzo[d]aza 4-3-yl]-fluorenone A mass spectrometry (ESI+): m/z = 336 [M+H]+ 320 (3,5-di- -4-hydroxy-phenyl&gt; (2/?,65)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methyl bridge-benzo[d]nitrogen[^3-yl] -曱阙C&amp;V CI A mass spectrum (ESr): m/z=404/406/408 (2CI) [M+H]+ 321 (3H-benzimidazol-5-yl)-(5-methoxy -3,3^8,83-tetrahydro-2H-1 -aza-cyclopenta[a]indol-1-yl)·methylamine starting material 5-methoxy-1,2,3,3&amp; , 8 batches of hexahydro-1-aza-cyclopenta[a] lanthanide WO 9200961 A mass spectrum is obtained in the (ES〇: m / z = 334 [M + H] + 135590.doc • 263 - 200927115

322 (3H-benzimidazol-5-yl)-(5-hydroxy-3,3a,8,8a-tetrahydro-2H-1-aza-cyclopenta[a]indol-1-yl)-fluorenone η. Mass Vi J or mass spectrometry (ESI+) as described in Example XIII: m/z = 320 [M+H]+ 323 (3H-benzimidazol-5-yl)-(1-decyl-10-aza- Tricyclo[7.2.1.0*2,7*]dodec-2,4,6-trien-10-yl)-fluorenone NA mass spectrometry (ESI+): m/z=318 [M+H]+ 324 ( 3H-benzimidazol-5-yl)-(1-methyl-10-aza-tricyclo[7.4.1.0*2,7*]tetrade-2,4,6-trien-10-yl) -Methyl ketone A mass spectrometry (ESI+): m/z = 346 [M+H]+ 325 (3H-benzimidazol-5-yl)-(5,8,9,10-tetrahydro-6H-6,10 -methyl bridge-pyrido[3,2-d]azepin-7-yl)-fluorenone 00)3⁄4) diastereomer as shown in racemic mixture A mass spectrum (ESI+): m/z = 319 [M+H]+ 326 (3H-benzimidazol-5-yl)-(3,5,9-triaza-tricyclo[6.3.1.0*2,6*]twelve 6),3 -Dien-9-yl)-methanone diastereomers racemic mixture A mass spectrum (ESI+): m/z=308 [M+H]+ 327 (1H-吲哚-3- (), (3,5,9-triaza-tricyclo[6.3 ·1.0*2,6*]dode-2(6),3-dien-9-yl)-indolone oxime Enantiomeric racemic mixture A mass spectrum (ESI+): m/z=307 [M+H]+ 135590.doc 264- 200927115 (3H-benzimidazol-5-yl)-(4-mercapto -3,5,9-triaza-tricyclic [6.3 · 1 .〇*2,6*]12-2(6),3-two -9-yl) ketone shown diastereomer racemic mixture 328 A mass spectrum (esD : m/z = 322 [M+H] + (1H-indol-3-yl H4-methyl -3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodec-2(6),3-dien-9-yl)-methanone 329 at 1ΐΡ Η A mass spectrometry ( ESI+): m/z = 321 [M+H] + a mixture of diastereomers as a racemic mixture (3 Η-benzimidazole _5 yl)-(7·ylamino-3,3,4 -trimethyl-2,3,4,4a,9,9a-hexahydro-gangrene[2,1 -b]»bipyridine-1 -yl)-carben 330 A mass spectrometry (ESr): n^z =376 [M+H]+ '-_ Some formulation examples will now be described 'where the term &quot;active substance&quot; has eight or more compounds of the invention, including salts thereof. In the case of a combination with one or an additional one of the active substances, the term "active" negative also includes 〇 additional active substances.

Example A Lozenges containing 100 mg of active substance Composition: 1 tablet contains the following: Active substance 100.0 mg Lactose 80.0 mg Corn starch 34.0 mg 135590.doc 265· 200927115 4.0 mg 2.0 mg Polyethylene. Dingling i Magnesium stearate 220.0 mg Preparation: The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of polyvinylpyrrolidine. The wetted composition was sieved (2.0 mm mesh size) and dried in a tray type dryer at 50°C, sieved again (1.5 mm mesh size) and a lubricant added. The final mixture is compressed to form an ingot. Tablet weight: 220 mg Diameter: 10 mm, double plane, faceted on both sides and notched on one side.

Example B Composition of a tablet containing 150 mg of active substance: 1 tablet contains the following: Active substance 150.0 mg Powdered lactose 89.0 mg Corn starch 40.0 mg Gelled cerium oxide 10.0 mg Polyvinylpyrrolidone 10.0 mg Stearic acid Magnesium 1.0 mg 300.0 mg Preparation: The tongue substance with lactose, corn powder and oxidized stone is moistened with 20% -266·135590.doc 200927115 polyvinylpyrrolidine solution and passed through a mesh. The particles dried at 45 ° C were again passed through a sieve of 1 1 5 nm and mixed with a prescribed amount of magnesium stearate. The mixture is pressed into a money agent. Tablet weight: 300 mg mold: 10 mm, flat

Example C Hard gelatin capsule composition containing 15 mg of active substance: ❹ 150.0 mg Approx. 1 8 0.0 ni g Approx. 87.0 mg 3.0 mg One capsule contains the following active substances corn starch (dried) lactose (powdered) stearin Magnesium sulphate ca. 420.0 mg Preparation: The active substance is mixed with excipients and passed through a sieve having a mesh size of Ο q υ· , 5 mm and uniformly mixed using a suitable device. The final mixture will be in a ^^ size hard gelatin capsule.

Capsule Filler: Approx. 320 mg Capsule Shell: Size 1 Hard Gelatin Capsule Example D Suppository containing 150 mg of active substance Composition: One suppository contains the following: 135590.doc -267- 200927115 Active substance polyethylene glycol 1500 Polyethylene Glycol 6000 Poly Emulsified Ethylene Sorbitan Monostearate 150.0 mg 550.0 mg 460.0 mg 840.0 mg 2,000.0 mg Preparation: After the suppository base is melted, the active substance is evenly distributed therein and the melt melt is poured into the cooling. In the mold.

Example E contains 10 mg of active substance in an amnesium composition: Active substance 10.0 mg 0.01 N hydrochloric acid

Double distilled water Add to 2.0 mL Preparation: Dissolve the active substance in the required amount of 0.01 N HCl, aliquot it with salt, sterile filter and transfer to 2 mL ampoules.

Example F An ampoule containing 50 mg of active substance Composition: Active substance 50.0 mg 0.01 N hydrochloric acid

Double steaming water Add to 10.0 mL 135590.doc • 268 - 200927115 Preparation: Dissolve the active substance in the required amount of 0.01 N HC1 with salt, sterile filter and transfer to 10 mL ampoules.

135590.doc -269-

Claims (1)

200927115 X. Patent application scope: 1. A compound of formula I: Wherein R represents an aryl or heteroaryl group, and the aryl group means a phenyl group or a naphthyl group, and the heterocyclic group means a stomach ratio of a heptyl group, a hexanyl group, a phenyl group, a ratio of a bite group, and a ruthenium group. a benzofuranyl group, a benzothienyl group, a quinolinyl group, an isoquinolinyl group, or a sulphate group, a coughyl group, a singly phenyl group, an η ratio bite group, wherein one or two CHs are replaced by hydrazine, or Mercapto, benzofuranyl, benzothienyl, quinolyl or isoquinolyl, wherein 1 to 3 CH are replaced by hydrazine, or 1,2-dihydro-2- oxo-η ratio Base, i, 4-dihydro-4-oxo--pyridyl, 2,3-dihydro-3-oxo-pyridazinyl, 1,2,3,6-tetrahydro-3,6 - Bis-oxy-pyridazinyl, 1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-indolylpyrimidinyl, 1,2,3,4-tetra Hydrogen-2,4-dioxy-pyrimidinyl, 1,2,dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxy Pyrazinyl, indanyl, indoleoxy-dihydroindenyl, 2,3-dihydroindenyl, 2,3-dihydro-1indole-isoindenyl, 2,3-di Hydrogen-2-oxo-indenyl, 2,3-dihydro-1-indolyl-isoindenyl, 2,3-dihydrobenzofuranyl, 2, 3-dihydro-2-side 135590.doc 200927115 oxybenzoxazolyl, 2,3-dihydro-2-oxo-benzoxazolyl, benzo[1,3]dioxan Cyclopentenyl, 2-formoxy-benzo[,3]dioxolyl, tetrahydro-naphthyl, 1,2,3,4-tetrahydro-carboline, 12, 3,4_tetrahydro_2_sideoxy-carbolyl, 1,2-dihydro-2-etheroxy-quinolinyl, anthracene, 4-dihydro-4-isoxyl-quinolinyl 1,2,3,4-tetrahydro-isoquinolinyl, U2,3, tetrahydrol_1-sideoxy-isoquinolinyl, i,2-dihydro-indole_sideoxy-iso Quinolinyl, 1,4-dihydro-4-sideoxy-carbolyl, anthracene, 2-dihydro-2-oxo-quinazolineyl, 1,4.dihydro-4_side oxygen 1, quinazolinyl, 1,2'3,4-tetrahydro-2,4-dioxy-quinazolinyl, anthracene, 2-dihydro-2_ oxaquinoxalinyl, 1, 2,3,4_tetrahydro_3_sideoxy-quinoxalinyl, 1,2,3,4-tetrahydro-2,3.di-oxy-quinoxaline, oxime-dihydro- 1-sided oxetazinyl, hydrazine, ^'tetrahydro-hydrazine, 4_di-oxy-pyridazinyl, guanidinyl, coumarinyl, 2,3-dihydro-benzo[M] Dioxolyl or 3,4-dihydro-3-inoxy-2/f_benzo[i,4]oxazine Wherein the above aromatic or heteroaryl ring is optionally substituted by one R4, one to four identical or different R5 and one R6, and all heteroaromatic rings are bonded to the carbonyl via a carbon atom, R2 and R3 together with the double bond to which they are attached Together, the benzo ring substituted by R7, R8 and R9, optionally substituted with R7, R8 and R9, optionally substituted with two substituents selected from R7, R8 and R9, is optionally substituted. And pyrazolo, benzophenone, pyridazine, pyrimidine or pyrazine and I35590.doc, if appropriate, substituted by pyrazole, imidazo, oxazole, thiazolo, isoxazole or isothiazolidine a 1,2,3-triazolo ring substituted by a phenyl group substituted by a Cl-4 group or, optionally, one to three R10 groups, in the ring or visually impaired state, representing oxygen, gas, indifference, hydrazine, alkyl, c2 -6 alkenyl, c2_6 alkynyl, hydroxy, Cm alkoxy, nitro, amine, CN3 alkylamino, bis(Cu alkyl)amine, indolozine-1-yl, 2-sided oxygen -Pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidine-i-yl, morpholine-4-yl, 3-oxo-morpholine-4-yl, piperazine -1-yl, 2-oxo-oxypiperazine -1-yl, 3-oxo-piperidin-1-yl, 4-(Ci_3 炫) base-0 bottom 0-yl-1-yl, 4-(Ci-4-alkyl)-peripipe Pyrazin-1-yl, 4-(C3_6cycloalkylcarbonyl)-piperazin-1-yl, 4-(CN4 alkoxycarbonyl)piperazin-1yl, 4-((^.4 alkylsulfonate) Mercapto)-piperazin-1-yl, 2-sided oxy-'(Cw alkyl)-piperazin-1-yl, 3-flank- 4- (Ci_3 alkyl)-pyrene-1 Base, C--3 alkyl-carbonylamino, (hetero)arylcarbonylamino, (hetero)aryl-Cw alkyl-carbonylamino, Cw alkoxy-carbonylamino, aminocarbonylamine , Cw alkyl-aminocarbonylamino, bis(Cw alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino, morphine-4 -yl-arylamino, 11-indolyl-ylamino, 4-(Ci_3 alkyl)-piperazin-1-yl-carbonylamino, Cw alkyl-sulfonylamino, amine Alkylsulfonylamino, C!-3 alkylamino-sulfonyl 200927115 Amino, bis(Ci.3 alkyl)amino-sulfonylamino, pyrrolidine-l-yl-based Amino, 11-Bottom-l-yl--glycosylamino, intimidyl-4-yl-retentylamino, n-yl-1-yl-transylamino, 4-(Ci.3 ())-benzin-1-ylsulfonylamino, (C!-3 alkoxy-carbonylamino)carbonylamino, (hetero)arylsulfonylamino, (hetero)aryl- C!·3 alkylsulfonylamino 5^(((^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ βΗalkyl)-(hetero)aryl-Cw alkanoyl-carbonylamino, N-CCualkyl)-Ci-3 alkoxy-carbonylamino, N-(amino)-Ci.3 Anthranylamino, N-(Ci_3 alkyl-amino)-Cualkylamino, N-[bis(Cw alkyl)aminocarbonyl]-Cualkylamino, N-fw alkyl) -(:, .3 alkyl-sulfonylamino, N_((••3 alkyl)-(hetero)arylsulfonylamino, alkyl)-(hetero)aryl-C 1 _3 • benzyl-continuous amino group, pendant oxy-imidazolidin-1-yl, 2,4-di-oxy-imidazolidin-1-yl, 2,5-di-oxy-imidazole-1 a 2-hydroxyl-hexahydropyrimidinyl-l-yl group wherein the nitrogen atom at position 3 of the above group is optionally substituted by methyl or ethyl, cyano, carboxy, C..3 alkoxy -carbonyl, aminocarbonyl, Cw alkyl-aminocarbonyl, bis(Cw alkyl)-aminocarbonyl, pyrrolidine-1- -carbonyl, piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, piperazine-1-yl-yl, 4-((^-3alkyl)-pyridin-1-yl- , (hetero)arylaminocarbonyl, N-(C-3-alkyl)-(hetero)arylaminocarbonyl, (hetero)aryl-C-3-alkylaminocarbonyl, NJCw alkyl Η) aryl-Cw 135590.doc -4-alkylaminocarbonyl, Cw alkyl-carbonyl, (hetero)aryl-carbonyl, carboxy-C^alkyl, C,.3 alkoxy-carbonyl- Cm alkyl, cyano-Ci.3 alkyl, amine base-Ci.3 alkyl, Ci.3 alkylamino group _ 匸1_3 alkyl, two ((^1-3 alkyl)_ Amino-based thiol-匚1.3-based, 11-by-1, π-1,4-yl-Wilyl-C.3 alkyl, cytidine-1-yl-rebel _Ci.3 alkyl, scared ·_4-yl-mono-Ci_3 alkyl, D-method-1-yl-subunit-Ci-3, 4-(Ci.3 alkyl)-Brigade-1·yl-number-Ci -3 院基' carboxy-Cw alkoxy, Cw alkoxy-carbonyl-CN3 alkoxy, cyano-Cw alkoxy, aminocarbonyl-Cw alkoxy, Cm alkyl-aminocarbonyl-Cw Alkoxy, bis(Cw alkyl)-aminocarbonyl-Cn3 alkoxy, pyrrolidin-1-yl-carbonyl-C!-3 alkyl-oxy, piperidin-1-yl-carbonyl-CN3 oxygen , morpholin-4-yl-carbonyl-Cw alkyl-oxy, piperazin-1-yl-carbonyl-Ci_3 alkoxy, 4-(Ci-3 alkyl)-piperidin-1-yl-yl - Ci_3 ethoxyl* hydroxy-Cw alkyl, C丨-3 alkoxy-Cw alkyl, amino-C,-3 alkyl, Cw alkylamino-Cw alkyl, di(cN3 alkyl Amino-(^_3 alkyl, pyrrolidin-1-yl-Cu alkyl, 2-sided oxy-pyrrolidin-1 -yl-C 1 -3 alkyl, britylene-1 -C 1 - 3 Alkyl, 2-tertiary-based cyano-1-yl-Cw alkyl, morpholin-4-yl-Cw alkyl, 3-sided oxy-morpholin-4-yl-Cw alkyl, piperazine -1-yl-Cw alkyl, 2-sided oxy-piperazin-1-yl-Cu alkyl, 3-sided oxy-piperazin-1-yl-Cw alkyl, 4-((^.3) Alkyl)-piperazin-1-yl-Cw alkyl, 2-oxo-4-(Cw alkyl)-piperazin-1-yl-Cw alkyl, 3-sided oxy-' (Chane 200927115 基)-派&quot;Qin-1-yl-Cl-3 Hyun•yl' Cw alkylcarbonylamino-Cw alkyl, arylcarbonylamino-Cw alkyl, hydroxy-Cw alkoxy, Cw alkane Oxy-Cw alkoxy, Cw alkylthio-Cw alkoxy, Cw alkylsulfinyl-Cw alkoxy, C!-3 alkylsulfonyl-(^.3 alkoxy, amine ke-Ci-3 alkoxy, Cw alkylamino-Ci.3 alkoxy , bis(C,-3 alkyl)-amino-C!.3 alkoxy, pyrrolidin-1-yl-Cu alkoxy, 2-sided oxy-pyridrolidin-1-yl-Cw Alkoxy group, piperidin-1-yl-Cw alkoxy group, 2-sided oxy group, ketone-1-yl-Ci.3 succinyl group, morphine-4-yl-Ci-3 saponin group, 3-oxo-o-lin-4-yl-C.3 alkoxy, D-methyl-1-yl-Ci_ 3 alkoxy, 2-oxo-α-endoxime-1·yl-Cw Oxyl, 3-tertiaryoxy-succinyl-1-yl-Ci-3 succinyloxy, 4-(Ci-3 alkyl)-azido-l-yl-Ci-3 alkoxy, 2- Sideoxy-4-(C!_3)-Phenyl-l-yl-yl-Ci-3 alkoxy, 3-o-oxy-'(Cu-alkyl)-piperazin-l-yl-c 】_3 alkoxy, ® Cw alkylthio, Cw alkylsulfinyl, Cn3 alkylsulfonyl, Cw alkylsulfonyloxy, (hetero)arylsulfonyl, (hetero) Sulfosyloxy, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, aminosulfonyl, CV3 alkyl-aminosulfonyl, di(Cw Alkyl)-aminosulfonyl, pyrrolidin-1-ylsulfonyl, piperidin-1-yl, synthetic base, chloropyrim-4-yl-continuation base, derivative-1-yl -The result is a base, 4-((^1.3烧基)-1[1 bottom 17 -1-yl-yield base 135590.doc -6- 200927115 monofluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, 2,2,2-trifluoro-1-hydroxyl Ethyl, 2,2,2-trifluoro-1-hydroxyindole-methylethyl, 2,2,2-trifluoro-1-hydroxy-1-(tri-l-methyl)ethyl, C3·6 Cycloalkyl, C3.6 cycloalkoxy, C3·6 ring-based Τι-3 alkyl, C3-6 cycloalkyl-Cw alkoxy, (hetero)aryl, (hetero)aryloxy, ( Hetero)aryl-Ci_3 alkyl, (hetero)aryl-c,-3 alkoxy, (hetero)aryloxy-Ci3 alkyl, or tetrahydrofuran-3-yl-oxy, tetrahydropyran-3 _ _ _ oxy, tetrapipetam-4-yl-oxy, tetrahydrofuranyl _c 3 alkoxy, tetrahydropyranyl-Cm alkoxy, wherein the above azetidin-1-yl, pyrrole The pyridine-1-yl and piperidinyl-1 yl moieties are optionally substituted with one or two groups selected from the group consisting of decyl, ethyl, decyloxymethyl, hydroxy or methoxy, and wherein the above piperazine- The 1-yl and morpholin-4-yl moiety is optionally substituted with one or two groups selected from methyl, hexyl or methoxyindenyl, and wherein the above (hetero)aryl is phenyl, naphthyl, Ruthenyl, fur Base, stilbene, tetradyl, butyl, thiol, benzoc-butyl, benzothienyl, quinolyl, isoquinolyl or phlodolyl, thiol, porphinyl ," than the bite group, in which 1 or 2 CH is replaced by hydrazine, or fluorenyl, benzoheptyl, benzothienyl, quinolyl, isoquinolyl, wherein 1 to 3 CH are replaced by hydrazine , or 135590.doc 200927115 1,2-dihydro-2-sideoxy-» than butyl, 1,4-dihydro-4-oxo-D-pyridyl, 2,3-dihydro-3 · pendant oxy-pyridazinyl, 1,2,3,6-tetrahydro-3,6-di-oxy-pyridazinyl, indole, 2-dihydro-2-oxo-pyrimidinyl, 3 , 4-dihydro-4-oxo-pyrimidinyl, iota, 2,3,4-tetrahydro-2,4-di-oxy-pyrimidinyl, 1,2-dihydro-2-oxooxy - pyrazinyl, 1,2,3,4-tetrahydro-2,3-di-oxy-pyrazinyl, 2,3.dihydro-2-isooxy-oxime, 2,3 -dihydrobenzofuranyl, 2,3-dihydro-2-oxo-oxime/f-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl, anthracene 1,2-dihydro-2.oxy-indolyl, 1,4-dihydro-4-indolyl-quinalyl, 1,2-dihydro-1.oxy-isophthalene Base, 丨, 4_ dihydrogen _ Sideoxy-carbolyl, 1,2-dihydro-2-oxo-quinazolinyl, L4-dihydro-4-o-oxo-quinazolinyl, tetrahydro-2,4·2 Sideoxy-quinazolinyl, 1,2-dihydro-2-oxoquinoxalinyl, ^,' and tetrahydro-3-oxo-quinoxalinyl, i, 2, 3, 4_tetrahydro-2,3_di-oxy _ 喧. Oxalyl, 1,2-dihydro-I-oxyl-bromide, 1,2,3, winter-tetrahydro-1,4-di-oxy-pyridazinyl, fluorenyl, fragrant Phytosyl, 2,3_indolodihydro[1,4]dioxanyl, 3,4-dihydroperoxy-2/indolyl[1,4]oxazinyl, and Wherein the above (hetero)aryl group is optionally substituted by one or two R1G which may be the same or different, 5]· the same or different R5 and R6 represent halogen, Cl.3 alkyl, 匸2 3 alkynyl, trifluoromethyl a group, a hydroxyl group, an alkoxy group, a cyano group or R5 together with R6, if bonded to an adjacent carbon atom, may additionally be a methylenedioxy group, a difluoroindenylenedioxy group, an ethylenedioxy group, a C3 5 Alkyl, or I35590.doc -8 - 200927115 R5, if combined with an adjacent carbon atom, can form a pyrazolo, imidazo, oxazole, thiazole, isoxazole, together with the hindered atom to which it is attached. And isothiazole ring, which is optionally substituted by Ci3 alkyl, trifluoromethyl, amine, Cw alkylamino, bis(Ci3 alkyl)amine, hydroxy, ci3 alkoxy, R7 represents fluorine, Chlorine, desert, moth, Cm alkyl, hydroxyl, c. 4. alkoxy, nitro, Amino group, CN3 alkylamino group, bis(Cl_3 alkyl)amino group, G pyrrolidinyl group, 2-sided oxy-β-pyrrolidin-1-yl group, pyridin-1-yl group, 2-side Oxy-piperidin-1-yl, morpholine-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-sided oxy-piperazin-1-yl, '(Cw-alkyl)-piperazin-1-yl, '(Cm alkylcarbonyl)-Bell-l-yl, 4-(C3.6 ring Pyridyl carbyl)-α-base-1-yl, 4-((::.4 alkoxycarbonyl)-piperazin-1-yl, 4-((:1_4 alkylsulfonyl)-branche -1--1-yl, 2-sided oxy-4-(Ci-3 炫)-派 ° Qin-1-yl, 3-sided oxy- 4- (Ci.3 Hyun "base" · slightly _ 1-based, V Cw alkyl-carbonylamino, (hetero)aryl-carbonylamino, (hetero)aryl-Cw alkyl-carbonylamino, Cw alkoxy-carbonylamino, aminocarbonylamine , C..3 alkyl-aminocarbonylamino, di(C,.3 alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamine , morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino, 4-((^.3 alkyl)-piperazin-1-yl-carbonylamino, Cw alkyl- Sulfhydrylamino, aminosulfonylamino Cw alkylamino-sulfonylamino, bis(Cw alkyl)amino-sulfonylamino, pyrrolidin-1-yl-135590.doc -9 - cross-branched amine, pie bite-1 -yl-arylamino, oxime-4-yl- hydrazino, piperazin-1-yl-sulfonylamino, alkyl)-piperazin-1-yl-sulfonyl Amino, (C^ alkoxy-carbonylamino)carbonylamino, (hetero)aryl aryl, (hetero)aryl-Cl.3 alkyl-alkylamino, alkyl hCw Alkyl-carbonylamino, alkyl)·(hetero)arylcarbonylamino, N-CCwalkyl)-(hetero)aryl-Cwalkyl-carbonylamino, Ν-((.3 alkyl) -C^ alkoxy-carbonylamino, N-(aminocarbonyl)-(^.3 alkylamino, alkyl-aminocarbonyl)-(^-3 alkylamino, N-[di (Cw alkyl)aminocarbonyl]-Ch alkylamino, N^C,.3 alkyl)-(:, .3 alkyl-sulfonylamino, N-(C1-3-alkyl) -(hetero)aryl fluorenylamino, N-(Ci_3)-(hetero)aryl-Cw alkyl-sulfonylamino, pendant oxy-° 嗤 bite-1 -yl, 2 , 4-di-oxy-π米嗤α1 -yl, 2,5-di-oxy-imidazole-1-yl, 2-sided oxy-hexahydropyrimidin-1-yl Wherein the nitrogen atom at position 3 of the above group is optionally substituted with a methyl group or an ethyl group, a cyano group, a (hydroxyimino)aminomethyl group, a (Cw alkoxyimino)amino group, a carboxyl group, C!.3 alkoxy-carbonyl, aminocarbonyl, C!-3 alkyl-aminocarbonyl, bis(CN3 alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl, piperidine-1- -carbonyl, morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl, 4-((^.3 alkyl)-piperazin-1-yl-carbonyl, C _3 alkyl-carbonyl, (hetero)aryl-carbonyl, mercapto-Ci-3 alkyl, Cw alkoxy-number-Cw alkyl, cyano- 200927115 Cw alkyl, aminocarbonyl-Cw alkyl, C, .3 alkane Base-aminocarbonyl-(^.烧基~二(6)-Oxylamino group-匚卜^基's mouth-bite-1-yl-singyl-Ci-3 alkyl, stagnation _1_yl-syl-Cl.3 Hyun, morpholin-4-yl-carbonyl-Ci_3 alkyl, piperazin-1-yl-carbonyl-Cl-3 alkyl, 4-((^-3 alkyl)-piperazin-1-yl-carbonyl- Cw alkyl, carboxy-CN3 alkoxy, C -3-alkyloxy-carbonyl-Cw alkoxy, cyano-C alkoxy, aminocarbonyl-Cw alkoxy, Cw alkyl-amino Carbonyl-Cw alkoxy, bis(Cw-alkyl)-aminocarbonyl-C--3 © alkoxy, pyrrolidin-1-yl-carbonyl-Cw alkyl-oxy, piperidin-1-yl - alkyl-Ci-3 gas-burning group, morphin-4-yl-sialyl-C!-3 fenyl-gas group, piperazin-1-yl-carbonyl-Cw alkoxy group, 4-(CN3 alkane Base)-piperidinyl-1-yl-sodium-anthracene 1.3 alkoxy group ^ group-〇1.3 alkyl group, (^1-3 oxa group _^!1-3 炫* base, amine group 匸1-3 烧基,^!1.3炫1基胺基-〇1_3炫&lt;基,二(匚1-3炫&gt;基)_胺基_Cw alkyl, pyrrolidin-1-yl-Cw Base, (: 丨_4 alkylcarbonyl-amino-Cw alkyl, NKCw alkyl)-(^.4 alkylcarbonyl-amino-C,-3β-based, 2-sided oxypyrrolidine -1·yl-Ci_3 alkyl, piperidin-1-yl-Cw , 2-sided oxy-piperidinyl-yl-Cw alkyl, morpholin-4-yl-C. 3-alkyl, 3-sided oxymorpholine-4-yl-Cw alkyl, piperidine嗪-l-yl-C1 -3 alkyl, 2 · pendant oxy-snap-1 -yl-c 1 _ 3 alkyl, 3-tertiary-yl, 2-sided oxy - 4- (Ci_3 Hyun·Ki)·Sp.-1-yl-Ci-3 alkyl, 3-sided oxy-4-(Ci-3 alkyl)-indol-1-yl-C!.3 alkyl, 135590. Doc -11 - 200927115 Hydroxy-Cw alkoxy, C _3 alkoxy-Cw alkoxy, C 】 3 thiol-Cw alkoxy, C, _3 alkyl sulfinyl-Cw Oxyl, CN3 alkylsulfonyl-Cl-3 alkoxy, amino-C!-3 alkoxy, CN3 alkylamino-Cl-3 alkoxy, di(C)·3 alkyl) ·Amino-〇1_3 oxime, β 比哈 bit _1_yl-Cl-3 alkoxy, 2-sided lactyl-0 piroxicam-1-yl-Ci-3 alkoxy, &quot底 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 3-Sideoxy-?indol-4-yl-Ci_3 alkoxy, succinyl-1-yl-C!-O3 alkoxy, 2-oxooxy-p-but-1-yl-Ci-3 Alkoxy, 3-oxooxy-slightly D-methyl-1-yl-Ci-3, oxy, 4-(Ci_3 alkyl)-Brigade_1_基_ Ci_3 alkoxy, 2-o-oxo-4-(Ci-3 alkyl)-Benqin-1-yl-Ci_3 alkoxy, 3-oxo-4-(〇1_3 alkyl)_' 0辰°Qin-1-yl-(^1-3 oxime, Cw alkylthio, C--3 alkylsulfinyl, Cw alkylsulfonyl, cN3 alkylsulfonyloxy , (hetero)arylsulfonyl, (hetero)arylsulfonyloxy, trifluoromethylthio, trifluoromethylsulfinyl®, trifluoromethylsulfonyl, aminosulfonyl Base, Cw alkyl-aminosulfonyl, bis(C,.3 alkyl)-amine base, 17 to bite-1-yl, ugly base, slightly bite-i-based-continuous Base, holly-4-yl-yield base, brigade _1_ base-based base, 4-(C _3 alkyl)-piperazin-1-yl-sulfonyl, difluorodecyl, Trifluoromethyl, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-ylethyl, 2,2,2-trifluoro-1-yl-1-yl 135590.doc • 12· 200927115 ethyl, 2,2,2·difluorosuccinic small (trifluoromethyl)ethyl, C3·6 cycloalkyl, C3-6 cycloalkoxy, 3-6 % alkyl-Cw alkyl, (: 3 6 cycloalkyl 3 alkoxy, -(hetero)aryl, (hetero)aryloxy, (hetero)aryl-Ci3 alkyl (hetero) ♦ ke-C]-3 alkoxy, (hetero)aryloxy cardinyl or tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yloxybutan-4- a base-oxyl group, a tetrahydron group, a group of alkoxy groups, a cyano-Cy alkoxy group, ❹ wherein the above (hetero)aryl group is as defined above, and the same or different R4R9 is a tooth. , Cl-3 alkyl, trifluoromethyl, hydroxy, Cw alkoxy, cyano or R together with 119 if otherwise bonded to an adjacent carbon atom may additionally be a methylenedioxy group, a difluoromethylene group Oxyl, #ethyldioxy, c35 alkyl, or R, if R is bonded to an adjacent carbon atom, may also be attached thereto The tetrahydrotetrahydropiperine atom forms a stupid, 吼°, 鸣 并, σ 嗓 、, 嗓 嗓 and azole, imidazo, triazolo, oxazole, thiazole, and dysentery And isothiazole ring, optionally as a 1 and / or one or two independently selected from the group consisting of halogen, Cl 3 alkyl, trifluoromethyl, amine, 3 alkylamino-(Cl_3) Substituted with a substituent of an amine group, a hydroxyl group or a Cw alkoxy group, L is L1 or L2, and L represents a halogen, a C丨j alkyl group, a C3 6 cycloalkyl group, a piperidinyl group, a trialkyl group, and an alkyl group. 1_((^_3院基基基)_n bottom bite, tetrahydrofuranyl, 135590.doc •13· 200927115 dioxin methyl, trifluoromethyl, cyano, nitro, amine, acetyl Amino, methylsulfonylamino, carboxyl, Cm alkoxycarbonyl, aminocarbonyl, &lt;^3 alkylaminocarbonyl, bis(Ci 3 alkyl)-aminocarbonyl, amine sulfonyl , methylthio, methylsulfinyl, decylsulfonyl, hydroxy, c丨-3, oxy, difluoromethoxy or trifluoromethoxy, L represents phenyl or phlo , a thiol group, a porphinyl group, a bite base, in which In any of these groups, 1 or 2 CH may be replaced by an N atom, or © dihydro-2-oxo-pyridyl, 1,4-dihydro-4-o-oxy-pyridyl, 2,3-Dihydro-3-o-oxy-pyridazinyl, 1,2,3,6-tetrahydro-3,6-di-oxyoxazinyl, 1,2-dihydro-2- side Oxy-pyrimidinyl, 3,4-dihydro-4-o-oxy-pyrimidinyl, 1,2,3,4-tetrahydro-2,4.di-oxy-pyrimidinyl or 1,2-di Hydrogen-2-oxo-pyrazine group, wherein the groups mentioned above under L2 are each optionally substituted with one or two groups independently selected from the group consisting of fluorine, gas, CN3 alkyl , difluorodecyl, trifluoromethyl, cyano, amine, ethoxymethylamino, methylsulfonylamino, carboxyl, Cw alkoxycarbonyl, aminocarbonyl, Cw alkylamine a group, a di(Ci.3 alkyl)-amino group, a trans group, a Ci_3 alkoxy group, a difluoromethoxy group and a trifluoromethoxy group, R10 is R1G' or R1(r', and R1Q_ Derivative of halogen, (: 丨_3 alkyl, difluorodecyl, trifluoromethyl, cyano, nitro, amine, etidylamino, methylsulfonic acid amine, fluorenyl, C, _4 alkane Oxycarbonyl, aminocarbonyl, Cw Aminocarbonyl, bis(CN3 alkyl)-aminocarbonyl, aminosulfonyl, methylthio, methyl 135590.doc • 14- 200927115 Sulfhydryl, decylsulfonyl, hydroxy, Cl · 3 alkoxy, difluoromethoxy or trifluoromethoxy, ρ10&quot;± - , ^ represents pyrrolyl, furyl, thienyl, pyridyl, wherein any of these groups, 1 or 2 CH is optionally substituted by N atom, or fluorenyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl' wherein any of these groups are '1 to 3 CH' n atom substitution, or phenyl, naphthyl, tetrazolyl, 1,2-dihydro-2-oxo-pyridyl, 1,4-dihydro-4-iso-oxy-pyridyl, 2,3 _Dihydro_3_sideoxy-pyridazinyl, 1,2,3,6-tetrahydro-3,6-di-oxy-pyridazinyl, dihydro-2-oxo-orone , 3,4-dihydro-4-yloxy, sigma, 1,2,3,4-tetrahydro-2,4-di-oxy-pyrimidinyl, 1,2-dihydro-2- Side oxy-pyrazinyl, 1,2,3,4-tetrahydro-2,3-di-oxy-pyrazinyl, 2,3-dihydro-2-indolyl hydrazino, 2 , 3-dihydrobenzofuranyl, 2,3-dihydro-2- side Base 1/7_ benzimidazolyl, 2,3-dihydro-2-sided oxy-benzoxazolyl, indole, 2-dihydro-2-epoxy-quinolinyl, iota, 4- Dihydro-4-oxo-quinolinyl, indole, 2•dihydro-1-o-oxy-isoquinolyl, 1,4-dihydro-4-o-oxy-indenyl, 1, 2-Dihydro-2-oxo-quinazolinyl, 1,4-dihydro-4-isooxy_啥 坐 坐 坐, 1,2,3,4-tetrahydro-2,4- Bis-oxy-quinazolinyl, anthracene, 2_digas·2_sideoxyquinoxalinyl, 1,2,3,4-tetrahydro-3-isooxy·indolyl, 1 , 2,3,4-tetrahydro-2,3-dihydroquinoxalinyl, 1,2-dihydro-indole_side gas-pyridazinyl, 1,2,3,4-tetrahydrogen -1,4-di-oxy-pyridazinyl, acetophenone, coumarinyl, 2,3-dihydro-benzo[1,4]dioxanthyl dihydrogen_3_ Phenoxybenzo[U]oxazinyl, 135590.doc -15- 200927115 and wherein any of the groups mentioned above at R10', as the case may be, independently, or two bases selected from the group consisting of Group substitution: dentate, Cl_3 alkyl, difluoromethyl, trifluoromethyl, cyano, nitro, amine, acetylamino, methylsulfonylamino, carboxyl, C1_4 alkoxy a carbonyl group, an amino group, a C 3 ·alkylaminocarbonyl group, a bis(Cl 3 alkyl)-aminocarbonyl group, an amine fluorenyl group, a methylthio group, a methylsulfinyl group, a methylsulfonyl group, Hydroxy, C丨·3 alkoxy, difluoromethoxy and trifluoromethoxy, X represents CH or hydrazine, ❹ melon, 11, 〇 represents 〇, 1 or 2, and wherein the bicyclic core structure of formula I Substituting independently, R11 to R, 4, wherein R11 represents fluorine, Cw alkyl, (hetero)aryl, hydroxy, Cn4 alkoxy 'cyano, carboxy, Cw alkoxycarbonyl, aminocarbonyl, Cl 4 Alkylaminocarbonyl, bis(Cw alkyl)-aminocarbonyl, hydroxy-Ci 4 alkyl or Cw alkoxy-C!.4 alkyl' wherein the (hetero)aryl is as described above, v R12 represents a fluorine SCw alkyl group, and the same or different R13 and R14 represent a Cm alkyl group, and at the same time, the above alkyl or alkylene moiety is a branched or non-branched bond, a tautomer thereof, and a stereoisomer thereof , a mixture thereof and a salt thereof, wherein the compound contained in the formulas π. 1 to II.8 is excluded 135590.doc -16 - 200927115 R is any substituent, alkyl, M2 and M3 are each independently hydrogen or alkyl, M4 is hydrogen or hydroxy, ❹ ❹ M5 is hydrogen or a meridine, and alkane is Μ represents phenyl 'which can pass through to three Selectively substituted with a group consisting of f, hydroxy, nitro, cyano, trifluoromethyl, methoxy; group of naphthyl or biphenyl, which may be selected from one to three selected from the group consisting of a group consisting of a nitro group, a cyano group, a tris, a methoxy group: a substituent; a pyridyl group which can pass through a dentate, a pyridyl group, a nitro group, a cyano group, a trifluoromethyl group, a methoxy group, and NR'R', substituted, wherein r, and R&quot; are each independently hydrogen or a substituent, or together with a nitrogen atom, form a 3 to 7 membered alicyclic ring, optionally having a double bond, quinoline, isoquinolinyl, 4 -cyclohexylphenyl, 4-sided oxy-4H- ρg D-endenyl, fluorenyl, benzoxenyl, benzofuranyl, 5,6,7,8-tetrahydro-naphthalene- 1-yl, 5,6,7,8-tetrahydro-naphthalen-2-yl, furyl, methylfuranyl, ethylfuranyl, methoxymethylfuranyl, thienyl, methylthienyl or Ethylthiophenyl, I35590.doc -17- 200927115 11.2 where 1 (: 1.4 alkyl, M2 is hydrogen or (^ _4 alkyl, ❹ M6 represents 2-ethyloxy-phenyl, 2-ethylamino-phenyl, 2-phenylamino-phenyl, 2-(2,3-dimethylphenylamino)-phenyl , 2-(3-methylthiophenylamino)-phenyl or pyridine group, Wherein R is nitrogen, Ci-6 alkyl group&apos; M1 is hydrogen or (^_4 alkyl, ◎ M4 is hydrogen or hydroxy, and M6 is phenyl, methylphenyl or methoxyphenyl HO HN 135590.doc -18- 200927115 Its tautomers, their stereoisomers, mixtures thereof and their salts. 2. A compound according to the claim ,, characterized in that it is selected from the formula </ br> to (7), wherein any bicyclic core structure of the formula 1.1 to 1.1 () is optionally substituted by R14, 1.1 The compound is excluded from the formula defined by the formula 111 to 11 as defined in claim 1 R' 1.3 1.4 In addition, 1.2 1.5 where the compounds of the formulae II.7 and II.8 as defined in claim 1 are excluded from the scope defined in 1.5, 135590.doc -19· 200927115 Wherein the compound of formula 3.3 as defined in claim 1 is excluded from the formula defined in formula 17, Wherein R1 to R3 and to Rl4 are as defined in the claim c, tautomers thereof, stereoisomers thereof, mixtures thereof and salts thereof. 3. The compound of claim 2, which is specifically selected from the group consisting of the formulas 1.1 to 1.10, and any bicyclic core structure of the gantry 1·1 to -10-10 is optionally substituted by R11 to R14, wherein R is not aromatic. Or a heteroaryl group, both of which are independently substituted by one R4, - to, the same or different r5 and one r6, and R and R together with the double bond to which they are attached represent a benzo ring or a pyrido ring, Both are independently replaced by R7, R8 and R9, or octaves and tb are slightly sturdy, healthy, and biting or ton, and any such groups are independently R7 and R8 or R8 and R9 are substituted, or 135590.doc -20- 200927115 means ° is more than sitting, smelling, and evil; "sit and sputum, sputum, and different '&gt; sputum or isothiazolidine ring, which Any group is optionally substituted by R7, R4 represents fluorine, gas, bromine, C!-4 alkyl, hydroxy, Cw alkoxy, nitro, amine, Cw alkylamine, bis(Cw alkyl) Amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1yl, 2-oxooxy-pyro-1-yl, morphine-4-yl , 3 - side oxy- - lin - 4 _ , β β -1 -yl, 2-tertiaryoxy-D- Chen noise-1 -yl, 3-side oxy-«»辰辰-1-yl, 4-(Ci.3院基)_°辰-1--1-yl, 4-(Ci_4 院 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基.4 alkoxycarbonyl)-piperazin-1-yl, 4-((:, .4 alkylsulfonyl)· Touridonic-1 -yl, 2-oxooxy-4 - (C1 · 3 ))-π bottom 嗓-1 -yl, 3-tertiaryoxy- 4- (Ci.3 alkyl)-° bottom ° Qin-l-yl' Cj-3 alkyl carbonylamino, (hetero) aryl Carbocarbonylamino, (hetero)aryl-Cw alkyl-carbonylamino, Ci.3 alkoxy-carbonylamino, aminocarbonylamino, Cw alkyl-aminocarbonylamino, bis(Cw) Aminomethylamino group, B-Bistol _ 1 -yl-peptidylamino group, β-end-11--1-yl-rebel® amino group, morpholin-4-yl-carbonylamino group, piperazine Pyrazin-1-yl-carbonylamino, 4-((^1-3alkyl)-Break-l-yl-yl-decylamino, hydrazine-l-alkyl-based mercaptoamine, (hetero) Sulfosylamino, (hetero)aryl-Cmalkyl-sulfonylamino, Ν-((^_3 alkyl)-CN3 alkyl-carbonylamino, N-iCw alkyl)-(hetero) Arylcarbonylamino group, -(hetero)aryl-Cw alkyl-carbonylamino, alkyl)-C^alkoxy-carbonylamino, N-(aminocarbonyl)alkylamino, alkyl-aminocarbonyl 135590 .doc -21 - 200927115 yl)-4-3 alkylamino, N-[di(C)-3alkyl)aminocarbonyl bcl3 alkylamino ' Ν-β decyl)-(^.3 Alkyl-sulfonylamino, NJCw alkyl)-(hetero)arylalkylamino, N-^·3 alkyl)-(hetero)aryl_Cl-3 alkyl Base, pendant oxy-imidazolidin-1-yl, 2,4-di-oxy-imidazolidinyl, 2,5-di- oxy-methylene quinone _ 1 ·yl, 2-sided oxy-6 Hydropyridin-1-yl, wherein the nitrogen atom at position 3 of the above group is optionally substituted by a mercapto group or an ethyl group, a cyano group, a carboxyl group, a Cw alkoxy-carbonyl group, an aminocarbonyl group, a Cl_3 alkyl-amine Carbocarbonyl, bis(CN3 alkyl)-aminocarbonyl, &quot;pyrrolidinyl-carbonyl, 2-(decyloxyindenyl)-»pyrrolidin-1-yl-carbonyl, 3-(methoxy oxime) -Pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, morphine-4-yl, slightly noisy-1-yl-yl, 4-(C)_3 alkyl) Pyrazine~1-yl-carbonyl, (hetero)arylaminocarbonyl N-(C)-3alkyl)-(hetero)arylaminocarbonyl, (hetero)aryl-Cw alkylaminocarbonyl, ® (Cw alkyl)-(hetero)aryl-Cw alkylamine Carbonyl group, Ci_3-carbo-rebel, (hetero)aryl-carbyl, carboxy-Cw alkyl, Cw alkoxy-carbonyl-Cw alkyl, cyano-Cw alkyl, aminocarbonyl 3 alkyl , Cw alkyl-aminocarbonyl _ Ci-3 alkyl, bis (Ci_3 alkyl) * amine thiol 〇ΐ 3 3 3 、 、 、 、 、 、 基 基 基 基 基 基 基 - - - - - - - - - - - -1-yl-prison base - Ci-3 alkyl, morphin-4-yl-subunit - Ci_3 alkyl, travel call - I-base-Tibet-Ci-3, 4-(C!- 3 烧基)·旅游-1-基-几基- C!-3烧基' 135590.doc 22- 200927115 Carboxyl-Cw alkoxy, C!_3 alkoxycarbonyl-Cw alkoxy, cyano -Ch alkoxy, aminocarbonyl-Cw alkoxy, cN3 alkyl-aminocarbonyl-Cw alkoxy, bis(Cm alkyl)-aminocarbonyl-Cw alkoxy, 11 pirole &lt;1 _1 _ _ _ _ _ 41.3 alkyl _ oxy, ° ° ° 1-1 - carbonyl-C!. 3 alkoxy, morpholin-4-yl-carbonyl-CN3 alkyl-oxy , piperazin-1-yl-carbonyl-q.3 alkoxy, 4-((^-3 alkyl)-piperidin 11 Qin-1-yl-prison- Cl.3 oxygenated * hydroxy-Cw alkyl, Cw alkoxy-Cw alkyl, amino-Cw ❹ alkyl, Cw alkylamino-Cw alkyl, bis(Cw alkyl)-amino-Cu alkyl, pyrrolidine -1-yl-C丨.3 alkyl, 2-sided oxy-pyrrole-1-yl-Ci-3, β-chen-1-yl-C!-3, 2-isoxy - Piperidin-1-yl-Cw alkyl, morpholin-4-yl-Cw alkyl, (methyl-morpholin-4-yl hCu alkyl, (dimethyl-morpholin-4-yl) -(:,.3 alkyl, 3-oxooxy-?·#-4-yl-Ci.3 alkyl, slightly-1-yl-Ci_3 alkyl, 2-oxo-anthracene_ 1 -yl-C1 -3 alkyl, 3-oxo-&gt;* bottom 嗓-1-yl-〇1-3 alkyl, 4-((^1_3 alkyl)- 派-1-yl-( 111.3 alkyl, 2-oxooxy-4 - (C丨-3 alkyl)-slightly β-methyl-1 -yl-C1 -3 entertainment I-based, 3-tertiaryoxy-4.-(C!-3 Anthracenyl)-Behindyl-Ci_3 alkyl, Cw alkylcarbonylamino-Cw alkyl, (hetero)arylcarbonylamino-Cw alkyl, hydroxy-Ci-3 alkoxy, Cw alkoxy- Cw alkoxy, Cw alkylthio-Cw alkoxy 'Cw alkylsulfinyl-Cw alkoxy, Cw alkylsulfonyl-CN3 alkoxy, amino-Cw alkoxy, ( :,-3 alkylamino-Cw alkoxy, di(C,.3 alkyl) -amino group 135590.doc -23- 200927115 Cu alkoxy, indole-Cl.3 alkoxy, 2-o-oxy-11-pyridin-1-yl-Cw alkoxy, piperidine -1-yl-Cw alkoxy, 2-sided oxy-Bent l-l-yl-C1 -3 alkoxy, morphine-4-yl-C 1.3 alkoxy, 3-sided oxy- La-4-ki-Ci-3 hospital oxygen, brigade. Qin-1-yl-Ci-3 alkoxy, 2-oxo-piperazine-1-yl-Cw alkoxy, 3-sided oxy-Brigade 11 Qin-1-yl-Ci-3 Base, 4-(Ci.3 alkyl)-slightly 1-yl-Ci-3 alkoxy, 2-oxo-oxy-4-(Ci_3 leu)-Behind-1-yl-Ci-3 Alkoxy, 3-o-oxy-4-((^.3 alkyl)-piperazin-1-yl-CN3 alkoxyalkyl, C!-3-alkylthio, Cw alkylsulfinyl, C, .3 alkylsulfonyl, (hetero)aryl fluorenyl, amine sulfonyl, Cw alkyl-aminosulfonyl, bis(Cw alkyl)-amine continuation, π ratio η each bite _1_ base - broth, slightly bite-1-yl-sulfonyl, morpholin-4-yl-sulfonyl, piperazine · 1 -yl-sulfonyl, 4- (C! -3 院基)--azizin-1_yl-continuary fluorenyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxyindol, 2,2,2-trifluoro-1 -hydroxyethyl, 2,2,2-trifluoro-hydroxymethylethyl, 2,2,2-trifluoro-hydroxy-hydrazine-(trifluoromethyl)ethyl, C3.6 naphthenic Base, c3_6 cycloalkoxy, C3·6 cycloalkyl-Cw alkyl, c3.6 cycloalkyl-Cl_3 alkoxy, (hetero)aryl, (hetero)aryloxy, (hetero)aryl Ci3 alkyl, (hetero)-aryl-Cl.3 alkoxy, Hetero)aryloxy-C丨·3 alkyl, or tetrahydrofuran-3-yl·oxy, tetrahydropyran-3-yloxy, tetrahydro 135590.doc •24- 200927115 0 An oxy group, a tetrahydro-β-buphthyl-Cl-3 alkoxy group, a tetrahydropyranyl-Cl-3 alkoxy group, wherein the above (hetero)aryl group is a phenyl group, a naphthyl group or a phlebyl group, tl Fumonyl, phenyl, "7-bite-based, fluorenyl, benzopyranyl, benzothienyl, quinolyl, isoquinolinyl or phlodolyl, furyl, thienyl, a pyridyl group in which one or two CHs are replaced by hydrazine, or a fluorenyl group, a benzofuranyl group, a benzothienyl group, a quinolyl group, an isoindolinyl group, wherein one to three CHs are replaced by hydrazine, Or 1,2-dihydro-2-oxo-pyridyl, 1,4-dihydro-4-o-oxo-0-pyridyl, 2,3-dihydro-3-oxo-pyridazine 1,1,3,6-tetrahydro-3,6-di-oxy-pyridazinyl, dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-isooxy - mouth bite, 1,2,3,4-tetrahydro-2,4-di-oxy-pyrimidinyl, 1,2-dihydro-2-oxo-pyrazinyl, 1,2,3 , 4-tetrahydro-2,3-di-oxy-pyrazinyl, 2,3-dihydro-2-indolyl-fluorenyl , 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-sidedoxy-¥ 1//-benzimidazolyl, 2,3-dihydro-2-oxo-benzo Oxazolyl, 1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-isooxy-carboline, 1,2-dihydro-1-yloxy -isoquinolyl, 1,4-dihydro-4-isooxy- fluorenyl, 1,2-dihydro-2-oxo-oxime, "isolinyl, 1,4-dihydro-4" - oxo-quinothiol, 1,2,3,4-tetrahydro-2,4-dioxy-quinazolinyl, 1,2-dihydro-2-oxoquinoxaline Base, i, 2,3,4-tetrahydro-3-o-oxy-quinoxalinyl, 1,2,3,4-tetrahydro-2,3-di-oxyl-quinoxalinyl, 1 ,2-dihydro-1-oxo-pyridazinyl, i,2,3,4-tetra 135590.doc -25- 200927115 Hydrogen-1,4-di-oxy-pyridazinyl, 咣° , coumarinyl, 2 3 -dihydro-benzo[1,4]dioxanyl or 3,4-dihydro-3-yl- 2,//benzo[1,4 a oxazinyl group and wherein any of the groupings described with respect to the (hetero)aryl group are replaced by _ or two R1G which may be the same or different, and R5 and R6 are independently selected from the group consisting of fluorine, gas, bromine, and C. Base, c2-3 alkynyl, trifluoromethyl, hydroxy, Cm alkoxy and cyanide The group is preferably selected from the group consisting of fluorine, chlorine, methyl, ethyl, ethynyl, trifluoromethyl, benzyl, methoxy and ethoxy, more preferably selected from the group consisting of fluorine, gas, methyl, ethynyl, The hydroxy group and the methoxy group or the right R5 and R6 are bonded to the adjacent carbon atom', which together may additionally represent a methylenedioxy group, a difluoromethylenedioxy group, an extended ethyldioxy group or a c3_5 alkylene group. Preferred for methylenedioxy, ethylidene-1,2-dioxy, propyl or butyl, more preferably methylenedioxy or ethyl-1,2-dioxy , the best exoethyl-1,2-dioxy, 〇7 R represents fluorine, gas, Cw alkyl, hydroxy, Cm alkoxy, schiffyl, amine, Cl-3 alkylamino, di (Ci -3 alkyl)amino group, D ratio slightly bite -1 -yl, 2 -sideoxy-° piroxime-1 -yl, pi-β _ 1 _ group, 2-side oxy-Brigade bite-1 -yl, morphine-4-yl, 3-oxo-o-lin-4-yl, 3-oxo-piperazin-1-yl, 4-((^.4 alkylcarbonyl)-piperazine -1-yl, Cw alkyl-carbonylamino, (hetero)aryl-carbonylamino, c,-3-alkoxy-carbonylamino, CN3 alkylamino-aminocarbonyl, two (CN3 Institute 135590. Doc •26- 200927115 yl)aminoamino group, 11 ratio slightly bite_ι_yl-arylamino, keto_ι_yl-ylamino, morphine-4-yl-amine Base, Ci_3, ketone, arylamino, Ci-3, arylamino- arylamino, bis(Ci-3 alkyl)amino-sulfonylamino, pyrrolidin-1-yl- Sulfhydrylamino, piperidin-1-yl-sulfonylamino, morpholin-4-yl-sulfonic acid amine, (hetero)arylsulfonylamino, NJCw alkyl)-C^ Alkyl-carbonylamino, alkyl)-(hetero)arylcarbonylamino, N-(CN3 alkyl)-Cw alkoxy-carbonylnonylamino, iMCw alkyl-aminocarbonyl 3 alkylamino , N-[di(Cw alkyl)aminocarbonyl]-CN3 alkylamino, IvKCw alkyl)-Cw alkyl-sulfonylamino, N-(C-3-alkyl)-(hetero) Arylsulfonylamino}cyano, (hydroxyimino)aminoindenyl, (cN3 alkoxyimino)aminomethyl, carboxyl, cN3 alkoxy-carbonyl, aminocarbonyl, C丨-3 alkyl-aminocarbonyl, bis(Cw alkyl)-aminocarbonyl, pyrrole-1-yl-rebel, ketone-1-yl-yl, morphine-4-yl-yl , ® Cw alkyl-carbonyl, (hetero)aryl Base, carboxy-Cw alkyl, Cw alkoxy-carbonyl-Cw alkyl, cyano-C!_3 alkyl, amino group-Ci_3 alkyl, Ci-3 alkyl-amino group-Ci- 3 burnt base, two (Ci-3 yard base)-amine base-C!_3 base, than bite-1-yl-syl-C!.3 base, travel bite-1-base-基-Ci_3 alkyl, morphin-4-yl-yiji _(^_3 alkyl) thiol-Ci-3 alkoxy, Ci_3 alkoxy-alkyl-Cw alkoxy, cyano-Cw Oxyl, aminocarbonyl _CU3 alkoxy, Cw alkyl - 135590.doc • 27- 200927115 Aminosyl-C 1 -3 alkoxy, bis(C 1 -3 leu)-amino group -C1 _ 3 alkoxy group, D piroxime-1 -yl-yl-Ci_3 alkyl group-oxy group, B bottom bite-1. group-rebel group - Ci-3 methoxy group, 淋 _ 4_基-叛基- Ci-3 院基-oxy, thio-(!!1.3 alkyl, 〇1.3 alkoxy _ 匚 1.3 院, amine-匸1-3 alkyl, Cw alkyl Amino-Cw alkyl, bis(C!-3 alkyl)-amino-Cw alkyl, pyrrolidin-1-yl-C丨·3 alkyl, 2-sided oxy-pyrene 0-基-Ci-3 alkyl, C 1-4-4 oxalylamino group _Ci_3 alkyl, Ν-〇 (Cu alkyl)-Ci-4 alkylcarbonyl-amino-C!-3 alkyl, 2 - side oxy - pie bite-1-yl - Ci_3, 3-terpoxy-morphin-4-yl-Ci-3 alkyl, hydroxy-Cw alkoxy, Cu alkoxy-Cw alkoxy, Cw alkyl sub-branched-Ci -3 alkoxy group, Ci_3 base base-Ci-3 yard base, bis(Ci-3 alkyl)-amino-Cu alkoxy group, 2-sided oxygen ratio leptin-1-yl group- Cl-3 alkoxy, 2-sided oxy-branched-l-yl-Cl-3 alkoxy, oxime-4-yl-Ci-3 alkoxy, 3-sideoxy- ·_4-yl-Ci-3 decyloxy, amine base, Ci-3 alkyl-amino group, bis(Ci-3 alkyl)-aminosulfonyl, pyrrolidine-1 -yl-sulfonyl, piperidine-yl-based, whey-4-yl-branched-difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C3.6 cycloalkyl, C3-6 cycloalkoxy, c3-6 cycloalkyl-Cw alkyl, C 3-6 cycloalkyl-C 1 -3 alkoxy 135590.doc -28 · 200927115 (heterogeneous) Aryl, (hetero)aryloxy, (hetero)aryl-Ci 3 alkyl, (hetero)aryl-c -3-alkoxy, (hetero)aryloxy-Ci 3 alkyl or tetrahydrofuran -yl-oxy, tetrahydropyranyl-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Ci.3 alkoxy Or tetrahydropyranyl-CN3 alkoxy, wherein the above (hetero)aryl is as defined above under Rule 4, which may be the same or different, gas, gas, evolution, Ci3 appearance, difluoromethyl, Hydroxy, Cw alkoxy or cyano, ❹ more preferably 'R8 and R9 independently represent fluorine, gas, methyl*, ethyl, isopropyl, trifluoromethyl, hydroxy, methoxy, ethoxy or cyano , preferably, ' R 8 represents a hydroxy or methoxy group, or if R 8 and R 9 are bonded to an adjacent carbon atom, they may additionally represent a methylenedioxy group, a difluoromethylene dioxy group, and a a bis-oxy group, a c35 alkyl group, or together with the carbon atom to which they are attached, form a benzo, pyrazine, &lt;1 azole φ, imidazolium, N-CCw alkyl)pyrazolo, N_( Ci3 alkyl)·imidazolium, triazolo, oxazolo, thiazolo, isoxazole or isothiazolo ring, wherein any five member aromatics are additionally substituted by L and any six members are cyclically L and/or one selected from the group consisting of fluorine, Ci 3 alkyl, trifluoromethyl, amine, c.3 alkylamino, bis(Ci 3 alkyl)amine, hydroxy or 〗3 alkoxy The substituent is mono- or di-substituted, and L represents fluorine, Cm alkyl, (: 3·6 cycloalkyl, piperidinyl, 丨-methyl-piperidinyl, 1-ethenyl-piperidinyl, tetrahydrofuranyl , trifluoromethyl, cyano, amino, ethinylamino, decylsulfonylamino, carboxy' ci3 135590.doc -29- 200927115 alkoxycarbonyl, aminocarbonyl, mercaptoaminocarbonyl , dimethylaminocarbonyl, an amine base, a trans group, a Cw alkoxy group, or a phenyl group, a β-bite group, a sedentary group, a β-callyl group, a whistle base or a 1,2-dihydrogen a 2-oxo-pyridyl group, optionally substituted with one or two groups independently selected from the group consisting of fluorine, gas, Cw alkyl, difluoromethyl, trifluoromethyl, cyano, Amine, etidylamino, methylsulfonylamino, carboxyl, Cw alkoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, hydroxy, methoxy, difluoro Methoxy and trifluoromethoxy fluorenyl, R10 represents fluorine, gas, bromine, CN3 alkyl, difluoromethyl, trifluoromethyl, cyano, nitro, amine, etidylamino, methyl Sulfhydrylamino, carboxyl, CN4 alkoxycarbonyl Base, aminocarbonyl, Cw alkylaminocarbonyl, bis(C!.3 alkyl)-aminocarbonyl, aminosulfonyl, methylthio, methylsulfinyl, decylsulfonyl , phenyl, hydroxy, Cl_3 alkoxy, difluoromethoxy or trifluoromethoxy, R11 represents fluorine, Cw alkyl, phenyl, hydroxy, Cw alkoxy, cyano, carboxy, Cw alkoxy Carbonyl, aminocarbonyl, Cw alkylamino-prison, bis(Cl_4 alkyl)-aminocarbonyl, hydroxy-Ci 4 alkyl or Ci 3 alkoxy-C 1 _4 alkyl, R represents defeat or oxime丨.3 炫基' is more preferably hydrogen, methyl or ethyl; and the same or different R13 and R14 represent Cw alkyl, tautomers thereof, stereoisomers thereof, mixtures thereof and salts thereof. 4. A compound according to claim 2, characterized in that it is selected from the general formula of formula 丨丨 to ^ 其中 wherein any bicyclic core structure of formulas 1.1 to 1.10 is optionally replaced by r&quot; to 135590.doc -30-200927115 R14, Wherein R1 represents phenyl, naphthyl, furyl, β-pyrazolyl, imidazolyl, β-pyridyl, pyrimidinyl. Biazinyl, pyridazinyl, fluorenyl, benzimidazolyl, &quot;borazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quin Oxazolinyl, acridinyl, quinoxalinyl, 2,3-dihydro-2-oxo-indenyl or tetrahydro-3-indolyl-quinoxalinyl, wherein any such group Optionally, independently by R4, one to four identical or different R5 and one R6, R and R3 together with the double bond to which they are attached represent a benzo ring or an alpha-pyridyl ring. Both are independently R7. And ... and substituted by a ruthenium 9, or a furan, pyrrolo, pyridazin, pyrimidine or pyrazino ring, wherein any of these groups are independently substituted by "and ... or rule 8 and R9; or吼 并, imidazo, oxazolo, thiazolidine, isoxazole or oxime. Sit and ring, wherein any of these groups are optionally substituted by R7, R4 represents fluorine, gas, bromine, cK4 alkyl , hydroxy, (^.4 alkoxy, amine, C, .3 alkylamino, bis(Cl3 alkyl)amine, pyrrolidine-i.yl, 2-sided oxy-pyrrolidine-1_ Base, piperidine_丨-yl, 2_sideoxy Piperidin-1-yl, morpholin-4-yl, 3-o-oxo-morpholine-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-side Oxy-piperazin-1-yl, 4-(Ci_3 alkyl)-0 s-ol-1-yl, fluorenyl-(C -4-alkylcarbonyl)-piperazin-1-yl, 4-(C3_6 ring Alkylamino)-benzin-1-yl, 4-((^4 alkoxycarbonyl)piperazinyl-yl, 4-((^-4 alkylsulfonyl)-piperazine-1 -yl, 2-oxooxy-4-((:, .3 alkyl)-piperazin-1-yl 3 - pendant oxy-4-(Ci-3 alkyl)-p-qin-1-yl , C--3 alkyl-carbonylamino, (hetero)arylcarbonylamino, (hetero)aryl-Ci.3 135590.doc •31 · 200927115 alkyl-carbonylamino, cN3 alkoxy-carbonyl Amino, aminocarbonylamino, C!-3 alkyl-aminocarbonylamino, bis(C!.3 alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino, piperidine -1-yl-carbonylamino, morpholin-4-yl-carbonylamino, piperazin-1 yl-carbonylamino, 3-alkyl)-piperazin-1-yl-carbonylamino, cyano, Carboxyl group, Ci.3 alkoxy-carbonyl group, aminocarbonyl group, Cw alkyl-amino group, mono(C 1 _ 3 alkyl)-amino group, D-Bistyl-1 -yl-yl group 2-(methoxy Base)-&quot;bilobidin-1-ylcarbonyl, 3-(decyloxymethyl)-»pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, morpholine-4 -yl-carbonyl, piperazine-buyl-carbonyl, 4-(Ci-3 alkyl)-piperazin-1-yl-carbonyl, Ν-β decylalkylindole) arylaminocarbonyl, alkyl)_ (hetero)aryl-CN3 alkylaminocarbonyl, Ci_3-alkyl-aryl, (hetero)aryl-yl, hydroxy-Cw alkyl, C].3 alkoxy-Cw alkyl, amine -Cw alkyl ' CN3 alkylamino-Cw alkyl, bis(Cw leumino)-amino-Ci_3, base ratio, p--1-yl-Cu-based, 2-sided oxy-β Bilo biting _ι_基-Cu ® alkyl, morpholin-4-yl-Cw alkyl, (methyl-morpholine-4-yl)-(:!.3 alkyl, (dimethyl-?啉-4-yl)-Ci.3 alkyl, 3-o-oxo-morpholin-4-yl-C1 -3 alkyl, Cl.3 alkylcarbonylamino-C,-3 alkyl, (hetero Arylcarbonylamino-cN3 alkyl, via-Cw alkoxy, Ch alkoxy-Cw alkoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, 2, 2, 2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-hydroxy-1-indenylethyl, 2,2,2-trifluoro-135590.doc -32- 200927115 1-hydroxyl -ι-( Trifluoromethyl)ethyl, (hetero)aryl, (hetero)aryl-C!.3 alkyl or (hetero)aryloxy, wherein the above (hetero)aryl group is phenyl, naphthyl, anthracene a base, a furyl group, a thienyl group, a pyridyl group, a fluorenyl group, a benzofuranyl group, a benzothienyl group, a quinolyl group and an isoquinolyl group, or a pyrrolyl group, a furyl group, a thienyl group or a pyridyl group, wherein 1 or 2 CH substituted by N, or fluorenyl, benzofuranyl, benzothienyl, quinolyl or isoquinolinyl' wherein 1 to 3 CH are replaced by N, and wherein the above (hetero)aryl Substituting R1G for substitution, R5 and R6 are independently selected from the group consisting of fluorine, gas, bromine, (: 丨.3 alkyl, C2.3 alkynyl, trifluoromethyl, hydroxy, CN3 alkoxy and cyano, or if R5 And R6 is bonded to an adjacent carbon atom, which together may additionally represent a mercaptodioxy group, a difluoromethylene dioxy group, a stretched ethyldioxy group or a C3.5 alkylene group, and R7 represents a gas or a gas. , Cl-4 alkyl, perylene, Cl-4 alkoxy, ® nitro, amine, Cw alkylamino, 2-sided oxy-pyrrolidin-1-yl, 2-sided oxy-peri Pyridin-1-yl, morpholin-4-yl, 3-sided oxy-morphin-4-yl, Cw alkyl-carbonylamino, (hetero)arylcarbonylamino, (:, _3 alkyl-sulfonylamino, N-(C)-3-alkyl)-(:,-3-alkyl-carbonyl Amino, N-CCw alkyl)-(hetero)arylcarbonylamino, alkyl)-C^alkyl-sulfonylamino, NJCw alkyl)-(hetero)arylsulfonylamino, Cyano, (hydroxyimino)aminomethyl, (Cw alkoxyimino)aminomethyl, carboxyl, 135590.doc -33- 200927115 Cw alkoxy-carbonyl, amine carbonyl, Cw alkane Amino-carbonyl, di(Cw alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, CN3 alkyl-carbonyl, Rebel-Ci-3 alkyl, Ci-3 alkoxy-mono-Ci-3 alkyl, cyano-Ci_3 alkyl, amino group _Ci-3 alkyl, C!-3 alkyl amine Alkyl group _^ι·3 alkyl group, bis(Cw alkyl)-aminocarbonyl-Cw alkyl group, pyrrolidin-1-ylcarbonyl-Ci_3 alkyl group, pie. Des-1-yl-hexyl-C.3 alkyl, morphin-4-yl-yl-C 1.3 alkyl, cyanocyano-Cw alkoxy, aminocarbonyl-Cw alkoxy, Cw Alkyl-aminocarbonyl-Cw alkoxy, bis(Ci.3 alkyl)-aminocarbonyl-cN3 alkoxy, pyrrolidin-1-yl-carbonyl-Cualkyl-oxy, piperidine-1 -yl-carbonyl-C 1 _ 3 alkoxy, 吓 - 4 -yl-yl-C 1.3 alkyl-oxy' hydroxy-Cw alkyl, CN3 alkoxy-Cw alkyl, cN4 alkyl Carbonyl-amino-Cw alkyl, N-iCw alkyl)-C!-4 alkylcarbonyl-amino-CN3 alkyl, 2-sided oxy-«&gt; pirox-1-yl-C! _3 alkyl, 2-sided oxy-wchen bite-1_yl-C 1 ·3 alkyl, 3-sideoxy-Merlin-4-yl-C 1 _ 3 炫 I base, thiol-C 1.3 Burning oxy, Ci.3 alkoxy-Cw alkoxy, aminosulfonyl, C!-3 alkyl-aminosulfonyl, bis(Cn3 alkyl)-aminosulfonic acid, trifluoro Methyl, difluoromethoxy, trifluoromethoxy, C3-6 cycloalkoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4 -yloxy, tetrahydro-O-furyl-Cl-3 alkoxy, tetrahydropyranyl-Cw alkoxy, (hetero)aryl or (hetero)aryloxy , 135590.doc -34- 200927115 wherein the above (hetero)aryl group for R7 represents stupid. Scorpion, succinyl, (tetra), (tetra), isoindolyl, (tetra)yl, (tetra)yl &quot;subsaltyl , a tris-s, a sulphate, a bite base, a thiol group, a pyridazinyl group or a triazinyl group, wherein any of these groups are as appropriate (iv). Mono- or di-substituted, the same or different RlR9 represents fluorine, gas, desert, c. 3. alkyl, trifluoromethyl, hydroxy, Cl. 3 alkoxy or cyano or ❹ Ο if R8 and R9 are bonded to Adjacent carbon atoms, which together may additionally represent a methylenedioxy group, a difluoromethylenedioxy group, an extended ethyldioxy group, a c3&lt;alkylene group, ^ or together with the carbon atom to which it is attached Form benzo,. Bis[rho]zepine, indolozole, imidazolium, N-(Cl_3 alkyl)-pyrazolo, N_(c]3 alkyl)-mi-indole, di-vomiting, &quot;bad saliva, 嗟β sit And 、 唾 恶 或 或 或 或 或 或 或 或 或 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , a trifluoromethyl group, an amine group, a Cw alkylamino group, a di(C|_3 alkyl)amino group, a hydroxyl group or a substituent of a C. alkoxy group, which is mono- or di-substituted, and L represents a fluorine or a methyl group. , ethyl, tert-butyl, c3-6 cycloalkyl, piperidinyl, 1-methyl-piperidinyl, 1-ethenyl-piperidinyl, tetrahydrofuranyl, trifluoromethyl, cyano, Amine, etidylamino, methylsulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonate Base, hydroxy, methoxy or phenyl, acridine, pyridazinyl, pyridazinyl, pyrimidinyl, 1,2-dihydro-135590.doc • 35- 200927115 2-sided oxy-pyridyl, Substituted by one or two groups independently selected from the following groups, as appropriate : fluorine, mercapto, trifluoromethyl, cyano, amine, arylamino, methyl arylamino, thiol, amino group, methylaminocarbonyl, dimethylamino Carbonyl, hydroxy and methoxy, R1G represents fluorine, gas, methyl, difluoromethyl, trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy or trifluoromethoxy, R11 represents Fluorine, CN3 alkyl, hydroxy or alkoxy, R12 represents fluoro or Cu alkyl, © R13 and R14 may be the same or different, CN3 alkyl, tautomers, stereoisomers thereof, mixtures thereof And a salt thereof. The compound of claim 2, which is characterized by being selected from the formula ι·ι to [ίο, wherein any bicyclic core structure of the formulas 1.1 to 1.10 is optionally substituted by r&quot; to R14, wherein R1 Represents phenyl, naphthyl, ° ratio "sit, beta-bite, ticky, naphthyl, benzofuranyl, fluorenyl, benzothienyl, benzimidazolyl, beta fluorenyl, benzene And tris-salt, benzo-β-β-based, benzopyrene-β-based, 啥琳®, iso-saltyl, quinodipine, peak bite, 喧 琳 基, 2,3-dihydro- 2-side Oxy-indenyl or 1,2,3,4-tetrahydro-3-o-oxo-quinoxalinyl' wherein any of these groups are independently independently passed through one R4 and one to four different or identical R5 Substituted, R2 and R3 are as defined in claim 4, and R4 represents fluorine, gas, CN4 alkyl, hydroxy, Cw alkoxy, amine, C 1 -3 hexylamino, and bis (C 1 ·3 1 yl)amino group, B bis-bita-1 _ group, brigade-1 _ group, morpholin-4-yl group, Cw alkyl-carbonylamino group, aminocarbonyl group, C!.3 alkane 135590.doc - 36- 200927115-Amino group, bis(cK3 alkyl)-aminocarbonyl, (N-methyl)-benzylaminocarbonyl, (N-methyl)-phenylaminocarbonyl, pyrrolidine _丨_yl-carbonyl, 2-(methoxymethyl)-pyrrolidinylcarbonyl, 3-(methoxymethyl)-0-pyrrolidin-1-yl-carbonyl, piperidine-yl-carbonyl, Porphyrin_4_yl-carbonyl, hydroxy-C.3 alkyl, Cw alkoxy_Ci3 alkyl, amino-Ci3 alkyl, c丨_3 alkylamino-c, ·3 alkyl, two (Cl 3 alkyl)_amino-Ci 3 alkyl, morpholine-4-yl-Cualkyl, (2-methyl-morpholine-4-yl)·(^_3 alkyl, (2,6 -Dimethyl-morpholin-4-yl)-(^-3 alkyl, 3-sided oxygen -morpholine_4_yl-methyl,pyrr-11 each bite_1_yl_Ci.3 alkyl, 2-sided oxy-pyrrolidin-1-yl-Cualkyl, C!-3 alkyl Alkylamino-Cw alkyl, phenylcarbonylamino-d.3 alkyl, amide "sodium-Cl.3 alkyl, triazolyl-Cw alkyl, trifluoromethyl, difluoromethoxy , trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-hydroxy-1-indenylethyl or 2,2,2-trifluoro 1-hydroxyl-l-(trifluoromethyl)ethyl, R5 and R6 are as defined in claim 4, R7 represents fluoro, gas, Cw alkyl, hydroxy, d.3 alkoxy, amine, ® c _3 alkyl-carbonylamino, Cw alkyl sulfonylamino, cyano, (hydroxyimino) aminomethyl, carboxyl, Cw alkoxy-carbonyl, aminocarbonyl, Cw alkyl -Aminocarbonyl, bis(Cw alkyl)-aminocarbonyl, hydroxy-Cw alkyl, Ci_3 alkoxy-Ci_3 炫 "基, (^1.3 Hyun 1 yl-mono-amino--111-3 Hyun , hydroxy-Cw alkoxy, Cw alkoxy-Cw alkoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, d.3 alkylcarbonyl, aminosulfonyl, Cw Alkyl-aminosulfonyl or di(C,.3 alkyl)-aminosulfonyl, 135590.doc -37· 200927115 (hetero) aryl, which is selected from the group consisting of phenyl, s-l-l-yl, fluorenyl, pyridyl, 1,2-dihydro- Ι-f -2 - oxo-oxime than bite, bitter base, pyridazinyl and 2,3-dihydro-2-methyl-3-oxo-pyridazinyl, each of which is optionally substituted by R1G ; R8, R9, L, R1. And R, R12 'R are as defined in the claim 4, tautomers thereof, stereoisomers thereof, mixtures thereof and salts thereof. 6. The compound of claim 2, which is characterized by being selected from the formula. To a formula wherein any bicyclic core structure of the formulae 1.1 to 1.10 is optionally substituted by Rn to R14, wherein R represents phenyl, pyrazolyl, pyridyl, benzofuranyl, fluorenyl, benzimidazole a carbazole group, a benzotriazolyl group, a benzothiazolyl group, a 2,3-monohydro-2-oxoindolyl group or a tetrahydro-3-yloxy-quinoxaline group, wherein any of these The group is independently replaced by one R4 and one to four different or identical R5, as appropriate. R and R together with the double bond to which they are attached represent a benzo ring or a pyrido ring, both of which are independently substituted by R7, ul. 8 and ulnar 9, as appropriate, or not to be compared with each other, and arbitrarily Feeding and licking and ringing, where any of these groups are replaced by independent institutions ^ (4) and ..., * Table 4 is more than 嗤 嗤 或 or 9 唾 并, both of which are replaced by ruler 7, R4 R and R6 are independently selected from the group consisting of fluorine, hydrazine, methyl, ethyl, ethynyl, trifluoromethyl, hydroxy, methoxy and ethoxy, or if R5 and R6 are bonded, as defined in claim 5 Adjacent adjacent %i atoms, together they may additionally represent sub-135590.doc •38· 200927115 methyldioxy, ethyl 丨, 2-methoxy, propyl or butyl, such as As defined in claim 5, R and R9 independently represent fluorine»A, fluorine gas, fluorenyl, ethyl, isopropyl, trifluoromethyl, silk, f gas group, ethoxy or cyano group, or a combination of fluorene To an adjacent carbon atom, it can additionally represent a methylene-oxy group and an ethyl group. , 2_dioxy, propyl, butyl or, together with the carbon atom to which they are attached, form benzo, noisy, 対I, imi, and N_(Cl.3) Sitting and licking, N_(Ci 3 burns the base and retortes, chews and sputum, sputum, sputum, or sputum, or any of the five members of the family The six members are optionally substituted or disubstituted with one L and/or one substituent selected from the group consisting of a gas, a methyl group, a tris, a methylamino group, a dimethylamino group, a trans group and a methoxy group. a tautomer, a stereoisomer thereof, a mixture thereof, and a salt thereof. 7. A compound according to claim 2, which is characterized by a formula selected from the group consisting of the formula: wherein any of the bicyclic core structures of the formulae 1.1 to M0 Substituted by the ruler &quot; to R14, wherein R1 represents 4-aminoindenyl-phenyl, 4-(morpholine-4-yl)phenyl, 4-aminophenyl, 4-hydroxyphenyl , 4-amino-3_fluoro-phenyl, 4-amino-% gas-phenyl, 4-amino-3,5·di-phenyl, 吲哚_3_yl, 吲哚·% Base, 吲哚-6-yl, benzimidazole _5-yl, carbazole _5-yl, benzothiazole _ 5- Or a benzothiazole-6-yl group, R2 and R3 together with the double bond to which they are attached are independently represented by R7, r8 135590.doc-39.200927115 and R9 substituted by a benzo ring or an anthracene ring or independently π is substituted with R and R or R8 and R9, and R4 represents qi, gas, methyl, thiol, f oxy, methylamino, chloro-4-yl, ethylamino, Amino group m, (N_f group)-propylamino group, (N-methyl)-benzylamino group, (N-fluorenyl)-phenylamino group, monomethylamino group -carbonyl, diethylaminocarbonyl, piperidinylcarbonyl, morpholine-4-ylcarbonyl, pyrrolidin-1-yl-carbonyl, 2-(decyloxymethyl)-pyrrolidine-1- -carbonyl, 1-hydroxy-ethyl, hydrazine-hydroxy-hydrazine-methylethyl, ® 2,2'2-trifluoro-1-hydroxy-1.methyl-ethyl, ethionylamino , phenylcarbonylaminomethyl, 2-oxo-pyrrolidinyl"-yl-methyl, morpholine-4-yl-indenyl, 3-oxooxy-indolyl-4-yl-methyl , i.sup._i_ylindenyl, tris-l-ylmethyl or (2-methylmorphin-4-yl)-fluorenyl, R and R are independently selected from the group consisting of fluorine, gas, sulfhydryl, ethynyl ,through And methoxy, or if 11 and R are bonded to adjacent carbon atoms', they may additionally represent a fluorenyldioxy or ethylidene-1,2-dioxy group. , 2_dioxyl, R7 represents fluorine, gas, methyl, hydroxy, decyloxy, amine, ethyl hydrazino, methyl hydrazino, cyano, (imine) Aminomethyl, carboxyl, ethoxycarbonyl, aminocarbonyl, decylaminocarbonyl, dimethylaminocarbonyl, ethionylaminomethyl, ethyl sulfonyl, aminosulfonyl, methylamine Sulfosyl, dimethylaminosulfonyl, phenyl, phenyl-1-yl, pyridin-3-yl, pyridin-4-yl, 1,2-dihydro-1-methyl-2- The side oxy-0 is more than the acetyl group, the 1,2-dihydro-1-methyl-2- oxo group is more than the -4- group, spray 135590.doc •40- 200927115 bite-4-yl, 2·Methyl, ..^^-5-yl, 6-methylpyridazin-3-yl, 2,3-dihydro-2-methyl-2-methyl-disoxazide, oxy- The azine-6-yl or methyl R8 represents a hydroxy or methoxy group and R9 is absent, or if R8 and R9 are bonded to an adjacent carbon source S Ψ A - # ^ ^ , they may additionally represent a methylene group - oxygen Or stretching an ethyl group or together with a sub-form to form a benzo- &quot; 嗓 嗓 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Thiazolopyrene is said to be *a more than six T ° 寺 本 并 并 及 及 吡 吡 吡 吡 吡 吡 吡 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或Substituted by l, .3 L represents gas, methyl, cyclopropyl, hydrazine, ethyl chloroformyl group, ethyl chloromethyl group, methyl aryl amine group, slow base, thiol group , 〒 oxy or 〇pyridinyl, pyridazinyl, pyrazinyl, 1-, polyfluorene i, 2-indol-2. pendantoxy-pyridyl, optionally substituted by one or two methyl groups R1() represents methyl, R represents methyl, ethyl, propyl, hydroxy or methoxy, R12 represents methyl or ethyl, R13 and R14 represent methyl, tautomeric n, and its The structure, the compound and its salt. 8. The compound of claim 2, which is characterized by a formula selected from the group consisting of enthalpy to oxime (7), wherein any bicyclic core structure of the formula 1·1 to 1.10 is optionally substituted by r11 to R14, wherein R1 is as claimed in claim 7 As defined, 135590.doc -41 - 200927115 R2 and R3 together with the bis-bonds to which they are attached, R7, R8 and R9, are independently defined by R4 as defined in claim 7, f-group The ethynyl group, the hydroxy group and the f-oxygen R5 and R6 are independently selected from the group consisting of fluorine, chlorine group or, if R5 and R6 are bonded to adjacent carbon atoms, the ethyl-1,2-dioxy group thereof is further extended to R7. As defined in request 7, Ο R8 represents a hydroxy or methoxy group and R9 is absent, or the formazan is bonded to an adjacent carbon atom, which together may additionally represent a subdiyl group:: or together with the carbon atom to which it is attached, as the case may be, , the second butyl group, the cyclopropyl group, the tetrachlorine biting _2_ group, the ethyl aryl group - the mother bite -4- group, the 〇 bite _3_ 某, 】 7 __ preparation, mw ^ * 丨, 2 -monohydro-1·methyl-2-oxooxypyridine·5-yl, pyridazine·4-yl, bis-azinyl or 5-methyl-pyridazin-2-yl substituted oxazolo, imidazole And or Ν_methyl-imidazolyl, optionally substituted by a methyl group, or, as the case may be, a methyl or dimethyl group substituted with a phenanthroline, s [ represents a thiol group, Tributyl, cyclopropyl, tetrahydrofuran-2-yl, ethionyl-piperidine-4-yl, pyridine-3-yl, pyridazine-3-yl, pyrazinyl, methylpyrazin-2-yl 12, dihydro-2-oxooxypyridin-5-yl, R1Q represents methyl, Rl1 represents methyl or decyloxy, Rl2 represents decyl or ethyl, R and R14 represent methyl, 135590.doc • 42- 200927115 9. 10 11. ❹ 12. 13. ❹ 14. Its tautomers, their stereoisomers, Mixtures and salts thereof. - A physiologically acceptable salt of a compound of at least one of claims 8 to 8 with an inorganic or organic acid or base. A pharmaceutical composition, such as an at least one of the requisites of claim (1) or a physiologically acceptable salt of claim 9, optionally with one or more inert carriers and/or diluents. A compound according to at least one of the claims 丨 to 8 or a physiologically acceptable salt as claimed in claim 9, including the claim! Or 2 excluded compounds for the treatment or prevention of diseases or conditions which may be affected by inhibition of the enzyme 11?-hydroxysteroid dehydrogenase (10) d, such as metabolic disorders. An at least one compound according to at least one of the claims 丨 to 8 or a physiologically acceptable salt of claim 9, comprising the use of the compound excluded from the claim 丨 or </ RTI> for use in the preparation of a therapeutic Or a pharmaceutical composition that prevents a disease or condition that is affected by inhibition of the enzyme ιΐβ-hydroxysteroid dehydrogenase (HSD) i, such as a metabolic disorder. a method for the preparation of a pharmaceutical composition, characterized in that a compound according to at least one of claims 1 to 8 or a compound according to claim 9 is prepared by a non-chemical method other than the compound excluded from claim 1 or 2. The physiologically acceptable salt is incorporated into one or more inert carriers and/or diluents. A method for the preparation of a compound according to any one of claims 1 to 8 or a physiologically acceptable salt of claim 9 in addition to a compound excluded from claim i or 2, characterized in that Or the presence of another additive in the presence of a compound, 135590.doc -43- 200927115 The groups R2, R3 and χ, m, 〇 are as defined in claims 1 to 8, reacted with Ri_c〇_Y prepared in situ from the corresponding carboxylic acid, where Y is a leaving group and R1 is as requested above Any of the protecting groups used may be simultaneously or subsequently cleaved, as defined in items 1 to 8, and if desired, subsequently converted to another invention by conventional methods suitable for the conversion of functional groups. a compound, if necessary, to resolve the compound of the formula I thus obtained to its stereoisomer; . ' If desired, the compound of the formula I thus obtained is converted into a salt, especially for medical use' Acceptable salt. 135 135590.doc 44- 200927115 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 135590.doc